Structural modification may be a way to make isoquinoline alkaloids efficient antibacterial drugs

Hui Wang; Yuanjing Zhao; Haoran Xu; Ping Wang; Simin Chen

doi:10.1016/j.arabjc.2023.105204

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Review article

11 2023

:16;

105204

doi:

10.1016/j.arabjc.2023.105204

Structural modification may be a way to make isoquinoline alkaloids efficient antibacterial drugs

Hui Wang, Yuanjing Zhao, Haoran Xu, Ping Wang^⁎, Simin Chen^⁎⁎

State Key Laboratory of South Western Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China

⁎Corresponding author. viviansector@163.com (Ping Wang),

⁎⁎Corresponding author. chensimin@cdutcm.edu.cn (Simin Chen)

Received: 2023-5-12, Accepted: 2023-8-12,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Isoquinoline alkaloids are a kind of small molecular compounds with isoquinoline structure which widely exist in natural plants. A large number of studies have confirmed that these substances have a variety of biological activities, such as antibacterial, anti-tumor, anti-hyperglycemia, anti-virus, anti-inflammation, regulation of metabolism and so on. However, the low solubility and over-mild action of these substances limit their application. Based on the pharmacodynamic characteristics, application prospect and clinical demand of isoquinoline alkaloids, we aim to review the antibacterial activity of isoquinoline alkaloids and find new modification sites and groups of isoquinoline alkaloids. to provide reference for the structural design of new drug molecules and fully explore its potential clinical application value.

Keywords

Isoquinoline alkaloids

Antibacterial activity

Structural modification

Synthesis method

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1 Introduction

Isoquinoline alkaloids are a class of small molecules of plant origin with a complex N heterocyclic structure. These substances have a wide range of structural types and its biological activity has attracted extensive attention from researchers worldwide since the 19th century(Shang et al., 2020). At this stage, more and more isoquinoline alkaloids with antimicrobial activities have been discovered, and it is of great significance to summarize the structural features and antimicrobial activities of these newly discovered alkaloids. According to the differences in structure and properties, isoquinoline alkaloids can be categorized into simple isoquinolines, bisbenzylisoquinolines, benzylisoquinolines, protoberberberines, aporphines and benzophenanthridines, etc. The structures of these compounds are shown in Fig. 1, and all of these compounds contain isoquinoline or tetrahydroisoquinoline as the base parent nucleus(Cheng, 2006).

Structure of various isoquinoline alkaloids.

Isoquinoline alkaloids and their derivatives have a wide range of biological activities, including antibacterial, anticancer, antiviral, and enzyme inhibition, among others. Antibacterial activity, in particular, has been a popular area of research in recent years. This class of compounds, according to the research reports, has good inhibitory effectiveness against both gram-positive and gram-negative bacteria (Amin et al., 1969; Basha et al., 2002; Cowan, 1999; Iwasa et al., 1996; Iwasa et al., 1998b ), such as Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Proteus mirabilis and Salmonella enteritidis, some of the components also showed inhibitory effects on yeast, suggesting that isoquinoline alkaloids have a high potential for antibacterial medication development (Zielińska et al., 2019). However, the relatively mild action of natural isoquinoline alkaloids, their low bioavailability, and potential toxic side effects have resulted in their limited use and underutilized clinical value (Xiao et al., 2018). In addition, the gradual emergence of resistance in pathogenic microorganisms with the widespread use of antibiotics has resulted in a decline in the clinical therapeutic efficacy of the existing drugs (Larsson and Flach, 2022).

Currently, rational structural modification is a vital approach for improving the biological activity of drugs, increasing bioavailability and reducing harmful side effects. Modification of current medications' chemical structures can not only increase efficacy and minimize toxicity, but also significantly shorten the development cycle of new treatments. This approach is still applicable to isoquinoline alkaloids, and structural modifications have significant value and impact on the broadening of the structural diversity of isoquinoline alkaloids, the enhancement of antimicrobial activity and selectivity, as well as the expansion of the antimicrobial spectrum. These benefits can help to promote the research, development, and application of antimicrobial drugs as well as help to address the issues of bacterial drug resistance.

In order to address issues with the application of isoquinoline alkaloids and provide references for the advancement of isoquinoline alkaloids as antimicrobial drugs with plant origin, we review the current work regarding the antimicrobial activities, conformational relationships, and structural modification methods of isoquinoline alkaloids in this paper.

2 Natural isoquinoline alkaloids and their antibacterial activity

Numerous research on isoquinoline alkaloids have been published, and new isoquinoline alkaloids are constantly being found. Table 1 lists the isoquinoline alkaloids that have been utilized as antibacterial medications and those that have been identified to have antibacterial.

The simple isoquinolines, protoberberids, and benzophenanthridines demonstrated high inhibitory effect against pathogenic microorganisms among the 38 isoquinoline alkaloids that have been found to have antimicrobial activity. However, because to issues with natural isoquinoline alkaloids, such as mild action and low bioavailability, have led to many limitations in their clinical use, and their clinical value has not been fully realized. Moreover, due to the widespread use of antibiotics, pathogenic microbes are able to develop resistance to them through gene mutation or horizontal gene transfer. Additionally, some bacteria have developed medication resistance over time, which has reduced the clinical therapeutic impact of already available drugs. In order to combat drug-resistant strains, it is necessary to consistently create new antimicrobial medications. The structural characterization of the 38 isoquinoline alkaloids in Table I reveals that these compounds exhibit specificity for the antimicrobial activity depending on the state of the N atom, the substituents at different positions, and the combination of the parent nucleus structure with the heterocyclic ring. This suggests that the structural modification of this class of compounds should be concentrated on these positions in the course of the subsequent research and development.

Isoquinoline alkaloids primarily affect various bacterial life activities by interfering with the bacterial energy metabolism, disrupting the bacterial biofilm system, cell wall, altering cell membrane fluidity, and affecting key proteins in bacterial life activities, such as urease, cytokinin Filamenting temperature-sensitive mutant Z (FtsZ), topoisomerase, and neuraminidase. For example, berberine down-regulates the expression of halI and halR genes in a dose-dependent manner, thereby interfering with the biofilm formation of Hafnia alvei, as well as destroying the structure of the cell wall and the integrity of the membrane to achieve the effect of killing methicillin-resistant Staphylococcus aureus. In addition to binding to sulfhydryl groups in the active site of urease and inactivating urease in a concentration-dependent manner, Coptisine interferes with urease maturation by inhibiting the activity of the urease accessory protein UreG and the formation of UreG dimers. Palmatine binds to neuraminidase (NA) proteins in a reversible, noncompetitive manner, thereby affecting the bacterial proliferation process. Sanguinarine affects the formation of the Z ring by inhibiting the assembly of FtsZ thereby inhibiting the cytokinesis process in Bacillus subtilis.

The cytokinesis protein FtsZ, a key bacterial protein involved in microbial cell division (Lock and Harry, 2008), is highly conserved among bacterial pathogens and has been shown to be critical for bacterial viability in genetic studies, making it a promising therapeutic target in bacterial infections. Due to the mild biological activity of natural isoquinoline alkaloids, and with the widespread use of antibiotics, the problem of drug-resistant bacterial infections is gradually increasing, which seriously affects the clinical efficacy of bacterial infection therapeutic drugs and patient safety. Therefore, the discovery of novel antimicrobial drugs from nature and modification of their original structures to effectively improve the biological activity of this class of compounds are the current hotspots in the study of the antimicrobial activity of isoquinoline alkaloids.

3 Isoquinoline alkaloids structure modification methods

Chemical structure modification of pharmacologically active natural or synthetic compounds is a common approach in drug design (Jin et al., 2016), and given that isoquinoline alkaloids have diverse structural types and significant antimicrobial activities, improving their properties by appropriate modifications, such as changing their solubility, enhancing their bioactivities, increasing their bioavailability, and decreasing their toxicity and side effects is one of the effective ways to explore the development of the clinical medicinal value of isoquinoline alkaloids. At present, the methods of drug structure modification mainly include semi-synthesis (a chemical synthesis method that uses natural products from plants and animals or microorganisms as the starting material to synthesize the target product), total synthesis (a method that uses various basic organic chemicals as the starting material to synthesize the target compound through a series of organic chemical reactions) and other chemical methods as well as biological methods, such as genetic engineering, cellular engineering and combinatorial biosynthesis. Among them, chemical modification methods are the main methods nowadays (Yan, 2021).

The structural study of 38 isoquinoline alkaloids in Table I revealed that the state of the N atom in the structure of these compounds, the substituents at different positions, and the binding of the parent structure to the heterocyclic ring show specificity for antimicrobial activity. In simple isoquinoline alkaloids, compound 8 has different substituents at C-1, C-6 and C-7, and exhibits excellent inhibitory activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa with MIC values of 3.12 µg/mL. Compound 10 has different substituents at N, C-3, C-7 and C-8. The MIC values for Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae and Pseudomonas aeruginosa are 4 μg/mL, 15 μg/mL, 15 μg/mL, 15 μg/mL, 64 μg/mL and 64 μg/mL, respectively. The MIC values for Candida albicans and Aspergillus fumigatus are all more than 64 μg/mL. Compound 11 with different substituents at the N, C-3, C-7 and C-8 positions showed excellent inhibitory activity against Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae and Pseudomonas aeruginosa showed excellent inhibitory activity with MIC values of 1 µg/mL, 5 µg/mL, 5 µg/mL, 5 µg/mL, 32 µg/mL and 64 µg/mL, respectively, and also showed some inhibitory activity against Candida Albicans and Aspergillus fumigatus with MIC values greater than 64 µg/mL. The MIC values were greater than 64 µg/mL. This suggests that C-1, N, C-3, C-6 and C-7 in simple isoquinoline alkaloids may be important sites for exerting antibacterial effects.

C-8, C-9, C-12 and C-13 of berberine in the protoberberine alkaloids have been shown to be the specific sites affecting their antibacterial activity. Compound 20 had different substituents at N, C-2, C-3, C-9 and C-10 positions and MIC value of 869 µg/mL against Staphylococcus aureus, compound 21 had different substituents at N, C-1, C-2, C-3, C-9 and C-10 positions and achieved an inhibition circle diameter of 15 mm against Staphylococcus aureus at a concentration of 10 mg/mL for a total of 500 µg. This suggests that the N, C-2, C-3, C-8, C-9 and C-10 positions of proberberberine analogues may be important sites affecting the antibacterial effect.

Among the benzophenanthridine alkaloids, compound 16 with different substituents at C-2, C-3, C-6, C-7 and C-8 positions showed a MIC value of 50 µg/mL against Staphylococcus aureus, compounds 17 and 18, with different substituents at positions C-2, C-3, N, C-7, C-8 and C-11, each had a MIC value of 3 µg/mL against the fungus Cladosporium herbarum MIC values were all 3 µg/mL, compound 19 with different substituents at C-2, C-3, C-7 and C-8 positions showed a MIC value of 264.7 µg/mL against Enterococcus faecalis. This suggests that the N, C-6, C-7, C-8 and C-11 positions of the benzophenanthridines may be important sites for exerting antibacterial effects. Some other classes of isoquinoline alkaloids are also included with different substitutions at different positions and exhibit different effects on their activities. From the above summary, we can find that the C-1, N, C-3, C-6 and C-7 of simple isoquinoline alkaloids, the N, C-2, C-3, C-8, C-9 and C-10 of protoberberberines, and the N, C-6, C-7, C-8 and C-11 positions of benzophenanthridines may be the important sites affecting the antimicrobial effect, which suggests that we should pay more attention to these positions during the structural modification of isoquinoline alkaloids.

By reviewing the relevant literature we have summarized the known structural modifications and chemical synthesis methods of isoquinoline alkaloids as follows.

3.1

3.1 Structural modification of simple isoquinoline alkaloids

We have identified above that C-1, N, C-3, C-6 and C-7 in simple isoquinoline alkaloids may be important sites to exert antibacterial effects, and the modifications of these sites in the available studies are as follows. (Kelley et al., 2012) synthesized isoquinoline-based derivatives from 6,7-Dimethoxy-3-hydroxy-1-methylisoquinoline and 6,7-dimethoxy-3-bromoquinolin-1-one. In vitro antibacterial assays revealed that the basic substituents at the C1-position in the isoquinoline derivatives were associated with increased antibacterial activity, with compound 1 (Fig. 2) showing MIC values of 2 µg/mL against Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus, Enterococcus faecalis and vancomycin-resistant Enterococcus faecalis showed significant inhibitory activity with MIC values of 8 µg/mL for both, and it was observed that the antibacterial activity of N-methylquaternium derivatives against Staphylococcus aureus increased with the lipophilicity of the C-3 position substituent, the MIC values of compound 2 (Fig. 2) against Staphylococcus aureus and Enterococcus faecalis were 1 µg/mL and 4 µg/mL, respectively, which were higher than those of berberine (MIC values of berberine against both Staphylococcus aureus and Enterococcus faecalis were greater than 64 mg/mL). Further mechanistic studies revealed that the antimicrobial activity of these derivatives was related to the polymerization of FtsZ, which inhibited the formation of the Z-ring by stabilizing the FtsZ polymer and inhibiting the GTPase activity, thereby inhibiting the GTPase activity by up to 85%. (Yang et al., 2013) obtained novel isoquinoline derivatives by chloromethylation, cyanidation of chlorine atoms and cyanohydrolysis of 1,3-benzodioxolane as the starting material. In vitro antimicrobial activity studies revealed that the presence of electron-withdrawing groups, such as halogen or trifluoromethyl groups, in N-substituted aryl groups in the obtained derivatives significantly enhanced the antimicrobial activity, whereas the presence of electron-donating groups, such as methyl and methoxy groups, significantly reduced the antimicrobial activity, and the isomers with aryl ortho substitution have stronger antibacterial activity than the isomers with para and meta position substitution. These results indicate that ortho substitution of electron-withdrawing groups on N-substituted aryl groups is beneficial for enhancing the antimicrobial activity of the compounds, such as fluorine ortho substituted aryl compound 3 (Fig. 2), which inhibited Alternaria alternate, Curvularia lunata and Fusarium oxysporum at a concentration of 50 µg/mL with 81.6 ± 2.4%, 94.3 ± 1.4% and 86.3 ± 1.9%, respectively. (Moreno et al., 2012) found that pyrroloisoquinolines have potential antibacterial activity and synthesized pyrroloisoquinolines by via double intramolecular cyclization conducted through a Bischler-Napieralski cyclodehydration-imine reduction sequence (Berenguer et al., 2009; El Aouad et al., 2009). In the subsequent modifications, it was found that compound 4 obtained after substitution of benzyl group at C-6 position in the parental structure of isoquinoline as well as compound 5 after substitution by 4-fluorobenzyloxy showed good antibacterial activity against Bacillus cereus, Staphylococcus aureus, Enterococcus faecalis, Salmonella enterica serovar typhii, Escherichia coli and Erwinia carotovora showed good antimicrobial activity, synthetic pathway (Fig. 2).

Reagents and conditions: (a) C6H5B(OH)2, Pd(OAc)2, XPhos, K2CO3, ACN/H2O, 100 °C; (b) Tf2O, Et3N, DCM, −78 °C; (c) potassiumt-butyl-N-[2-(trifluoroboranuidyl)ethyl] -carbamate, PdCl2(dppf), Cs2CO3, dioxane/H2O, 102 °C; (d) TFA, DCM, 0 °C to rt; (e) 1,3-di-Boc-2-(trifluoromethylsulfonyl) guanidine, Et3N, CH2Cl2, 37 °C; (f) TFA, DCM, 0 °C to rt; (g) Tf2O, Et3N, DCM, −78 °C; (h) 2-benzyloxy- 3,4-dimethoxyphenylboronic acid, Pd(OAc)2, XPhos, K2CO3, ACN/H2O, 90 °C; (i) H2, Pd/C, MeOH; (j) Tf2O, Et3N, DCM; (k) 4-biphenylboronic acid, Pd(OAc)2, XPhos, K2CO3, ACN/H2O, 95 °C; (l) MeI, sealed tube 100 °C; (m) Five Step Method: Chloromethylation, cyanidation of chlorine atoms, hydrolysis of cyano groups, reduction of carboxyl groups, bromination of hydroxyl groups; (n) (CH2O)n, con, HCl, POCl3, 26–30 °C, 4–5 h; (o) Ar-NH2, H2O, SDS, reflux2-3 h; (p) 1: CuCl2-H2O, EtOH, reflux, 10 h 2: 40%HBr; (q) Benzyl chloride, K2CO3, EtOH, reflux, 6 h; (r) Nitromethane, AcOH, reflux, NH4OAc, 12 h; (s) LiAlH4, THF/Et2O, N2, reflux 2 h; (t) Ethyl succinyl chloride, 5%NaOH, CH2Cl2, rt, 12 h; (u) POCl3, CH2Cl2, N2, reflux, 6 h; (v) NaBH4, MeOH, rt, 2 h; (w) Concd HCl-EtOH1:1, reflux, 3 h; (x) p-Fluorodichloromethane, K2CO3, EtOH, reflux 12 h.

(Iwasa et al., 2001) obtained isoquinoline derivatives by Pictet-Spengler reaction using dopamine as the initial substance, and two Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, two Gram-negative bacteria, Salmonella enteritidis, Escherichia coli and one fungus Candida albicans were used as test organisms, the antibacterial effect of all derivatives was tested by liquid dilution method. The experimental results revealed that N-quaternization and benzylation of the C-6 and C-7 hydroxy groups also enhanced activity, while propylation increased activity to a lesser extent. Among the tested derivatives, 1-propyl-6,7-dibenzyloxy-N-benzyl-3,4-dihydro-isoquinoline compound 6 (Fig. 3) showed the highest inhibitory activity against all tested strains, and its inhibitory effect on Gram-positive bacteria was better than that of Gram-negative bacteria, the MIC values were 3.9 µg/mL for Staphylococcus aureus, Bacillus subtilis, Staphylococcus epidermidis, and Candida albicans, and 15.6 µg/mL for Escherichia coli. (Galán et al., 2013) used another classic intramolecular Bischler–Napieralski cyclodehydration to generate the isoquinoline core(Cabedo et al., 2001; Cabedo et al., 2009), using β-(3,4-dimethoxyphenyl) ethylamine as the starting material to synthesize a variety of isoquinoline-based derivatives with different substitutions at C-1, N, C-6 and C-7, with three Gram-positive bacteria: Bacillus cereus, Staphylococcus aureus and Enterococcus faecalis and three Gram-negative bacteria: Salmonella enterica serovar typhi, Escherichia coli and Erwinia carotovora were tested for 24 h in vitro antibacterial activity at a dose of 0.2 mg. The results showed that 1-pentanol-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-like compound (THIQ-1) showed the highest inhibition against the tested strains tested, but showed no activity against Bacillus cereus. Subsequently, the group continued to optimize the structure of THIQ-1 at the C-1 position with THIQ-1 as the lead compound, and synthesized both ester derivatives and carbamate derivatives. It was found through antibacterial experiments that the two methylene groups in the phenylpropanoic acid ester derivatives were placed between the ester group and the substituted aromatic ring, which had a greater impact on the enhancement of antibacterial activity of the compounds, and a similar effect existed in the carbamate derivatives. Among them, compound 8 with 1-pentyl linked to fluorophenyl propionate, compounds 12 and 13 linked to halogenated phenyl groups and compounds 10 and 11 linked to phenethyl carbamate showed the most significant fungicidal effect, chlorinated derivatives like chlorobenzoate and chlorophenylpropanoate esters (7 and 9, respectively) and chlorophenethyl carbamate 11, exhibited the greatest antifungal activity. With compound 11 at a dose of 0.2 mg on the tested the inhibition circle diameters of the tested strains were Bacillus cereus (14.67 mm), Staphylococcus aureus (16.33 mm), Enterococcus faecalis (17.0 mm), Salmonella enterica serovar typhi (18.33 mm), Escherichia coli (17.67 mm), Erwinia carotovora (18.33 mm), Escherichia coli (12.33 mm) synthetic pathways (Fig. 3). (Chen et al., 2023) Synthesized isoquinoline derivatives obtained by [4 + 2] cycloaddition and ring opening/aromatization method using 2-Chloro-5-iodopyridine and mesitylene as the starting materials, 3-arylisoquinolines were found to be a potential antifungal core structure by in vitro and in vivo antifungal experiments, in which compound 14 (Fig. 3) exhibited potent antifungal activity with an EC₅₀ value of 3.65 µg/mL against Physalospora piricola.

Reagents and conditions: (a) C3H7CHO/H2O; (b) Bncl, K2CO3; (c) I2, AcOK; (d) Methyl adipoyl chloride, 5%NaOH, CH2Cl2, rt, 2 h; (e) POCl3, CH3CN, reflux, 1 h; (f) MeI, Acetone, reflux, 3 h; (g) NaBH4, MeOH, rt, 2 h; (h) LiAlH4, Et2O, THF, reflux, 2 h; (i) 4-DMAP, Et3N, CH2Cl2, rt, 5 h; (j) TfOH, mCPBA, CH2Cl2, 60 °C, 30 min; (k) Furan, tBuOK, toluene, r.t., 15 h; (l) BBr3, CH2Cl2, −78℃, 2–3 h; (m) MeI, K2CO3, THF, reflux; (n) C10H7Bpin, Pd(dba)2, Xphos, Na2CO3, Toluene/H2O/EtOH, 110 °C, 12 h; (o) CH3OTf, N2, 0 °C to r.t., 12 h.

In addition to the modifications at these sites C-1, C-3, N, C-6 and C-7, the modifications at other sites of the simple isoquinoline alkaloids as follows. (Lu et al., 2020) Modification at the C- 5, C- 8 and N-positions of tetrahydroisoquinoline reveals a positive correlation between the antimycobacterial activity against Mycobacterium tuberculosis and the lipophilicity of the compound. Subsequently, a series of N-substituted 5,8-disubstituted tetrahydroisoquinoline derivatives synthesized from 8-(4-methylpiperazin-1-yl)isoquinoline, in which the C- 5 position was replaced by a large substituent (e.g., benzyl) and with N-methylpiperazine at the C- 8 position exhibited stronger activity, while the –CO- and –COCH₂- linkers in the N-substituted derivatives were less effective than –CH₂- or –CONH-, suggesting that the positioning of a terminal aromatic ring is important for target binding. All of these compounds are strongly lipophilic, with clogP values ranging from 2.59 to 7.12. Among them, compound 15 (Fig. 4) showed the strongest inhibitory activity against Mycobacterium tuberculosis with MIC value of 1.2 µg/mL. Mechanistic studies revealed that compound 15 showed a strong inhibitory activity against the ATP synthase of Mycobacterium tuberculosis (IC₅₀ = 1.8 µg/mL), although not as strong as the clinical ATP synthase inhibitor bedaquiline (IC₅₀ = 0.55 µg /mL), it has a faster microsomal clearance and a higher safety profile than bedaquiline, clearance in HLM (human liver microsomes), MLM (mouse liver microsomes) was 50, 65 µL/min/kg protein, respectively. (Zhu et al., 2017) Bioactivity of N-position aryl-substituted, C-5-substituted simple isoquinoline derivatives synthesized using 2-(3,4-dimethoxyphenyl)acetic acid as the initializing was evaluated against five phytopathogenic fungi(Fusarium solani, Fusarium graminearum, Valsa mali, Cercospora lunata, Colletotrichum gloeosporioides) by the mycelial growth rate method, most of the compounds showed mean EC₅₀ values between 7.87 and 20.0 µg/mL against the fungi, with compounds 16 and 17 (Fig. 4) showed good inhibitory activity with mean EC₅₀ values of 3.5–5.1 µg/mL, significantly better than sanguinarine and chelerythrine, two well-known natural fungal inhibitors, and speculated that the compound may be affecting the activity of Δ ¹⁴ reductase during ergosterol biosynthesis thereby exhibiting antifungal activity (ergosterol has a variety of important roles in fungi, including cell membrane stabilization, cell wall formation, and mycelial growth).

Reagents and conditions: (a) NBS, DMF, 20 °C, 3 days; (b) nBuLi, THF, −78 °C, 5 min, then MeSSMe, −78 °C, 2 h; (c) NaCNBH3, BF3. Et2O, MeOH, reflux, 22 h; (d) 4-nitrophenylchloroformate, pyridine, DCM, 2–20 °C, overnight; (e) DMF, 75 °C, 26 h; (f) dry Br2, dry CH2Cl2; (g) NaBH4, I2, dry THF, 0 ∼ 40 °C; (h) (HCHO)n, TFA, r.t; (i) n-BuLi, dry THF, −78 °C; (j) DDQ, dry MeOH, dry CH2Cl2; (k) TMSBr, Bu4NBr, dry toluene, 80 °C; (l) Ar-NH2, Dioxane; (m) 0.1MK2HPO4, PH6, 50 °C.

In addition, (Guzman et al., 2013) the ability of tetrahydroisoquinoline derivatives with different substitutions at C-1, C-5 and C-8, obtained by phosphate-mediated condensation of Pictet-Spengler phenethylamine with aldehydes, to assess growth inhibitory activity against Mycobacterium Tuberculosis by using spotted culture growth inhibition (SPOTi) assay (Evangelopoulos and Bhakta, 2010). Finally, it was found that among the synthesized derivatives 5-bromo-8-hydroxy substituted derivatives 18, 19 (Fig. 4) showed a significant increase in antituberculosis potency compared to tetrahydroisoquinoline. Pharmacokinetic analysis revealed that both compounds showed excellent solubility (18, 0.8 mg/mL; 19, 0.3 mg/mL), and membrane permeability showed that compound 19 was moderately permeable in the MDCK monolayer assay (3.2 × 10^-6 cm/s), whereas compound 18 was slightly less permeable (1.7 × 10^-6cm/s). Further mechanistic studies revealed that the synthesized tetrahydroisoquinoline derivatives destabilize Mycobacterium cell walls and affect Mycobacterium viability by affecting the activity of ATP-dependent MurE ligase, a key enzyme involved in the early stages of cell wall peptidoglycan biosynthesis, which is capable of influencing cell wall stability (Guzman et al., 2015).

3.2

3.2 Structural modification of protoberberine alkaloids

This kind of alkaloid is composed of two isoquinoline rings and can be divided into berberine and protoberberine according to the degree of oxidation of the mother nucleus. These alkaloids such as berberine and palmatine(Gao et al., 2008; Jin-Ming et al., 2008) have been found to have good antibacterial activity and have been developed as antibacterial drugs. We have identified above that the N, C-2, C-3, C-8, C-9 and C-10 sites in the structure of these alkaloids may be important sites affecting the exertion of antimicrobial action, and the modifications of these sites in the available studies are as follows. The low bioavailability of berberine, which exerts its activity mainly in the gastrointestinal system, has severely limited its application and development (Li et al., 2008). Studies on its low bioavailability have all found that the N atom in the structure plays an important role in the transport and absorption of berberine in the organism. The N atom causes berberine to be somewhat lipophobic, making it difficult to be absorbed in the gastrointestinal tract. Therefore, its bioavailability can be significantly improved by introducing lipophilic substituents to improve its lipophobicity.

(Lo et al., 2013) performed lipophilic substitution at the C-9-O position of berberine and drug metabolism experiments showed that the bioavailability of the derivatives obtained by lipophilic substitution at the C-9-O position was significantly improved, with compound 20 (Fig. 5) showed a great advantage in terms of permeability to cell membranes. Furthermore, dihydroberberine has been found to be more effective in vivo and to have a better bioavailability than berberine. However, berberine was the predominantly absorbed form in rat plasma (90%), because dihydroberberberine may undergo acid-catalyzed aromatization to berberine after absorption in vivo, which may affect the bioavailability of dihydroberberberine. (Cheng et al., 2010) synthesized three 8,8-dialkyl dihydroberberberine derivatives using berberine as the starting material. Subsequent experimental results showed that 8,8-dimethyldihydroberberberine 21 (Fig. 5) possessed better aqueous solubility, stability, bioavailability and was not converted to berberine in vivo compared with dihydroberberberine. The water solubility of compound 21 (81 mg/mL) was superior to that of dihydroberberine (less than1 mg/mL), and the bioavailability of compound 21 was 10.03%, which was much higher than that of dihydroberberine 2.65%, and under acidic conditions (pH 2), within 6 h, the content of dihydroberberine decreased by 17%, whereas compound 21 showed no significant decrease. In addition, (Teng et al., 2019) presented the first C-9-O-aryl-substituted derivatives of berberberine 22 (Fig. 5) using tetrahydroprotoberberine as the starting material via copper-catalyzed cross-coupling reactions with aryl iodides, which substantially improved the lipophilicity of this class of compounds.

Reagents and conditions: (a) 20–30 mmHg, 190 °C, 1–2 h; (b) K2CO3, alkyl or terpenyl bromide, acetonitrile, reflux, 4–8 h; (c) 20% KOH; (d) POCl3, Reflux; (e) RMgCl; (f) HCl/EtOAc; (g) Demethylation; (h) Ar-I, CuI, Praziquantel acid, K2CO3, DMSO, 100 °C, 24 h; (i) I2, DMSO, 60 °C; (j) NaBH4, 5% NaOH/K2CO3, CH3OH, rt, 3 h; (k) 40% Glyoxal, HOAc/CH3CN, reflux, 6 h; (l) Methanol/HCl (2:1 by vol), rt, 24 h; (m) 2,4-Dimethoxybenzylamine/R2NH2, 100–116 °C, 4–32 h; (n) 1:1 HCl/CH3OH, rt, 24 h, (o) R3COCl､Pyridine､CH3CN, 40–91 °C, 3–72 h; (p) 20–30 mmHg, 195–210 °C, 40 min; (q) R1COCH2Br､KOH, DMF, 68–75 °C, 4–24 h; (r) p-CH3C6H4-NH2, 95–120 °C, 4–72 h; (s) Vacuum (20–30 mmHg), Heating (200–220 °C), 20 min; (t) 1. Alkyl bromide, dry N,N-dimethylformamide. Potassium carbonate anhydrous, 80 °C, Stirring, 2–4 h, 2. Silver chloride, hot methanol, stirring; (v) NaBH4 (10 equiv.), MeOH, reflux, 48 h; (v) CF3COOH, CH2Cl2, room temperature 1.5 h, then HCl, MeOH.

Related studies demonstrated that 9-acetoxycyclic berberine 23 (Fig. 5) showed potent activity against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus, with MIC values of 1–8 µg/mL. (Fan et al., 2018) synthesized a large number of novel cyclic berberine derivatives substituted at the C-9 position, including ethers, amines and amides, using berberine as the starting material, and evaluated their antibacterial efficacy. In vitro antibacterial experiments showed that the introduction of a suitable substituent at the C-9 position could substantially enhance the efficacy against methicillin-resistant Staphylococcus aureus. Among them, compounds 24 and 25 (Fig. 5) showed potent antimethicillin-resistant Staphylococcus aureus efficacy (MIC values of 4, 2 µg/mL, respectively), and exhibited more stable pharmacokinetic profiles. Compounds 23, 24 and 25 were incubated with blood isolated from Sprague-Dawly (SD) rats for 420 min and then samples were extracted to test for the residual amount of the drug, which was 58.0 and 57.2%, respectively. The residual percentage of compounds 24 and 25 was 58.0 and 57.2%, respectively, which was much higher than that of compound 23. Preliminary mechanistic studies suggest that compound 25 acts on bacteria by accelerating the breakage of their DNA. Compound 25 changed pET-32a DNA from the CCC form to the open loop form, and cleavage activity and drug concentration correlated well. (Fan et al., 2020) modified the C-9 position of palmatine and examined the antibacterial activity against six metronidazole-resistant Helicobacter pylori species. The structure–activity relationships suggested that the introduction of a suitable secondary amine substituent at the C-9 position might be beneficial to improve the antibacterial activity. Among them, compound 26 (Fig. 5) showed the strongest activity against metronidazole-resistant strains with MIC values of 4–16 µg/mL, which was superior to palmatine (MIC values of 64–256 µg/mL), and had a higher safety profile with LD₅₀ values greater than 1000 mg/kg. Mechanistic studies revealed that compound 26 was able to bind to the binding site in the hydrophobic pocket of urease activity, and in vitro experiments revealed that compound 26 inhibited cutanea urease activity in a dose-dependent manner, with a half inhibitory concentration (IC₅₀) of 6.76 ± 1.86 μg/mL, which was much lower than that of PMT (greater than32 μg/mL). In addition,(Li et al., 2015) designed and synthesized a series of novel palmatine derivatives with alkyl or N-heterocyclic alkyl structures at the C-9-O position of palmatine and tested their antibacterial activity in vitro, the findings demonstrate that for an aliphatic chain with the same number of carbon atoms, the more complex the spatial structure, the more favorable the antimicrobial activity is; substituting a hydrophilic group at position C-9-O does not promote an increase in antimicrobial activity. The C-9-O alkyl-substituted palmatine derivatives had stronger antibacterial activity than the N-heterocyclic alkyl-substituted derivatives and found that the LD₅₀ values decreased with the alkyl side chain The alkyl-substituted compounds showed a 2- to 64-fold increase in antibacterial activity over palmatine against Gram-negative bacteria and a relatively weaker inhibition of Gram-negative bacteria than Gram-positive bacteria. Compound 27 (Fig. 5) showed the highest antibacterial activity among all the synthesized derivatives with MIC values of 3.91 µg/mL and 7.8 µg/mL against Staphylococcus aureus and Bacillus subtilis, respectively, which were significantly better than palmatine (MIC values of 250 µg/mL and 500 µg/mL), while compound 28 (Fig. 5) was the least toxic with an LD₅₀ value of 945.7 mg/kg (palmatine LD₅₀ value of 670.1 mg/kg). (Cheng et al., 2014) synthesized N-methyltetrahydroprotoberberines (29, 30) from protopines showed excellent antibacterial effects, and it was found that planar molecules with a high level of arylation or molecules to be positively charged positively influenced the antibacterial effect. The compounds 29, 30 were shown to be effective against Staphylococcus aureus, Staphylococcus Gallinarum and Escherichia coli with MIC values of 250/125/62 µg/mL, 31.25/31.25/250 µg/mL, respectively.

In addition to modifications at these sites of the protoberberine alkaloids, N, C-2, C-3, C-8, C-9 and C-10, other sites were studied as follows. (Iwasa et al., 1998a) introduced alkyl/phenyl at the C- 8 and halogen at the C-12 of berberine. Staphylococcus aureus, Bacillus subtilis, Salmonella enteritidis, Escherichia coli and Candida albicans were used as test bacteria. It was found that the length of aliphatic chain or fatty chain at the C-8 of berberine and the introduction of halogen atoms at the C-12 affected its antibacterial activity, in which the MIC values of n-butyl substituted compound 31 at the C-8 position (Fig. 6) were 15.6, 31.2 and 31.2 µg/mL for Staphylococcus aureus, Bacillus subtilis and Salmonella enteritidis, respectively, which were significantly better than berberine (MIC values of 250, 1000 and 500, µg/mL), but against Escherichia coli, Candida albicans, the antibacterial activity of C-8 alkyl-substituted berberine did not always increase with the extension of the alkyl side chain; the antibacterial activity of the C-8-phenyl-substituted derivatives was slightly decreased compared to the C-8-alkyl-substituted derivatives. Among the series of derivatives synthesized, 12-bromo-8-n-hexyl berberine 32 (Fig. 6) was 64, 256, 128, 16 and 32 times more active than berberine against the above-mentioned test organisms, the activities against Staphylococcus aureus, Salmonella enteritidis and Candida albicans were 8, 16 and 128 times of kanamycin sulfate, respectively. (Park et al., 2006) synthesized a series of benzyl-substituted berberine derivatives at the C-13 position and examined their antifungal activity against various human pathogenic fungi, of which compound 33 (Fig. 6) exhibited the highest antifungal activity against Candida albicans, Candida tropicalis, Candida Lusitaniae and Candida Krusei with MIC values of 4, 1, 8 and 4 µg/mL, respectively, which were significantly better than berberine (MIC values of 128, 16, 128 and 32 µg/mL).

Reagents and conditions: (a) C4H9MgI, Et2O; (b) Br2, AcOH; (c) RMgI/ET2O; (d) Br2 10 eq.mole/AcOH; (e) acetone, 5 N NaOH, rt, 1 h; (f) various benzyl bromide, NaI, CH3CN, 80 °C, 4 h; (g) AgCl (1 equiv), MeOH, 60 °C, 2 h; (h) 5 N NaOH, Acetone, rt, 1 h; (i) Various bromides, Nal, CH3CN, 80 °C, 4 h, 65%-77%; (j) Various amines, EtOH/conc, HCl, 45 min.

In addition, (Iwasa et al., 1998b) introduced alkyl groups at the C-13 position of berberine and tested the inhibitory activity against Bacillus subtilis and Salmonella enteritidis, showing that the antibacterial activity increased with increasing length of the C-13 aliphatic side chain, and found that the lipophilicity of the derivatives caused by substituent modifications seemed to affect the antibacterial activity. Among the synthesized 13-alkyl derivatives of berberine 13-Hexylberberberine (34) and 13-hexylpalmatine (35) showed MIC values of 7.8 and 15.6 µg/mL against Bacillus subtilis, and 3.9 and 7.8 µg/mL against Salmonella enteritidis, respectively. 3.9 and 7.8 µg/mL against Bacillus subtilis and Salmonella enteritidis, respectively, and the antimicrobial activities were stronger than that of berberine. (Wang et al., 2017) introduced substituted phenyl and alkyl substituted amino groups at the C-9, and C-13 positions of berberine, respectively, and evaluated their antibacterial activity against Staphylococcus aureus, including the Newman strain and multidrug-resistant strains, for their antibacterial activity. Among them, compound 36 (Fig. 6) showed the strongest inhibitory activity against the growth of Newman strain with MIC value of 0.78 µg/mL, which was superior to berberine (MIC value greater than 25 µg/mL). In addition, compounds 36, 37 and 38 (Fig. 6) showed highly inhibitory activity against 17 multidrug-resistant Staphylococcus aureus strains with MIC values of 0.78–1.56 µg/mL, and subsequent studies found that these compounds were not significantly toxic to human fibroblast viability at the lowest inhibitory concentrations, showing a good safety profile.

(Jeyakkumar et al., 2017) synthesized novel benzimidazolyl tetrahydroproberberine substituted at C-9 and C-12 positions by direct cyclization of tetrahydroproberine with aldehydes and o-phenylenediamine under metal-free aerobic oxidation, which showed generally improved antibacterial activity compared to non-C-12 substituted dihydroproberine, with the C-12 position substituted by 5-fluorobenzimidazolyl derivative 39 (Fig. 7) exhibited broad-spectrum antibacterial activity with MIC values of 4.4 µM, 17.4 µM and 14.5 µM against Bacillus subtilis, Shigella dysenteriae and Bacillus typhi, respectively, which were significantly stronger than berberine (berberine against Bacillus subtilis, Shigella dysenteriae, Shigella dysenteriae and Bacillus typhi with MIC values of 1147.3 µM, 1147.3 µM and 458.9 µM, respectively). Further studies revealed that the hydroxyl group, the nitrogen atom on the benzimidazole ring and the methylenedioxy group in the structure of compound 39 were able to form hydrogen bonds with the amino acid residues of ASN 555, HIS 365 and ASP 323 of topoisomerase IA, and that compound 39 was also able to insert into calf thymus DNA and cleave pBR322 DNA, which may be the main reason for its potent biological activity. (Song et al., 2018) synthesized C-8 and C-13 position substituted palmatine derivatives using quaternary ammonium salts as lead compounds and determined the in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli and Candida albicans, all derivatives showed good inhibitory activity against Staphylococcus aureus, and it was found that the antibacterial activity increased significantly with the increase of carbon content of the C-13 substituents. The cytotoxicity of extending the carbon chain decreased when less than 5 carbon, but once more than 6 carbon or more, the corresponding compounds showed greater cytotoxicity. Among them, the quaternary ammonium salts 13-(ω-ethoxycarbonyl) heptylpalmatine 40 (Fig. 7) and 8-oxo-13-(N-nonyl) aminomethylhydropalmatine 41 (Fig. 7) showed good antibacterial activity with MIC values of 7.81 µg/mL and 15.63 µg/mL against Staphylococcus aureus, respectively.

Reagents and conditions: (a) 190 °C/Vacuum, EtOH/conc. HCl, 45 min; (b) NaBH4, MeOH, rt, 5 h; (c) a. HM/TFA120 °C, 5 h, b. 10%HsSO4, 90–100 °C, 2 h; (d) Pro-phenylenediamineⅡ/Ⅲ, DMF/H2O, 80 °C, 12 h; (e) K2CO3, NaBH4, rt; (f) ClCOOEt or Br(CH2)nCOOEt. n greater than 0, NaI, reflux; (g) KOH, Air, 80 °C; (h) DMF, POCl3, 0 °C, then110 °C; (i)CH3I, CsCO3; (j) primaryamine, HOAc, reflux, then NaBH4; (k) 100 °C, 8 h; (l) NaBH4, Methanol, reflux, 5 h; (m)Glyoxal, formicacid, CuSO4, Hydrochloric acid, 100 °C, 5 h; (n) Methanol, H2O, CaO, rt, 2 h; (o) Ethanol, HCl, rt, 0.5 h.

The alkylation and acylation on C-9, C-10, C-11 and C-12 of berberine can increase the activity and improve the bioavailability, but the methoxy at the C-9 position can form electrostatic attraction with the quaternary ammonium ion in the structure, which leads to the decrease of the positive charge of berberine and thus affects the bioavailability of berberine.(Shan et al., 2013) Pseudo berberine 42 (Fig. 7), obtained by switching the methoxy group of berberine from the C-9 position to the C-11 position, had a decreased positive electronegativity due to the increased distance between the quaternary ammonium ions and the methoxy group, which resulted in a lower affinity for Pglycoprotein, and significantly longer retention time than berberine in Caco-2, HL- 7702, and C2C12 cells, after equal-dose administration in rats.

3.3

3.3 Structural modifications of benzophenanthridine alkaloids

The structure of benzophenanthroline alkaloids is mainly composed of methyl benzophenidine core and several methoxy or methylenedioxy substituents, which are mainly distributed in Papaveraceae, Corydaceae, Rutaceae and Ranunculaceae. For example, sanguinarine, chelerythrine and their corresponding derivatives have been proved to have antiviral and antibacterial activities (Móricz et al., 2015). We have identified above that the N, C-6, C-7, C-8 and C-11 positions in the structure of this class of alkaloids may be important sites to exert antibacterial effects, and the modifications of these sites in the available studies are as follows. (Miao et al., 2011) synthesized five kinds of derivatives from sanguinarine and chelerythrine by reduction, oxidation and nucleophilic addition of imine bond. The antibacterial activities of all compounds were screened with Staphylococcus aureus, Escherichia coli, Aeromonas hydrophila and Pasteurella multocida as test bacteria. The results showed that the imine bond in sanguinarine and chelerythrine was the determinant of antibacterial activity, and the substitutes at the C-6, C-7 and C-8 positions affected the antibacterial activity of sanguinarine and chelerythrine against different bacteria. Compound 45 (Fig. 8) significantly enhanced the inhibitory effect on Staphylococcus aureus with a MIC value of 12.5 µg/mL, but, the effect on Escherichia coli and Aeromonas hydrophila was not significantly enhanced compared with sanguinarine. (The values of sanguinarine to Staphylococcus aureus, Escherichia coli and Aeromonas hydrophila MIC are all 25 μg/mL).

Reagents and conditions: (a) NaBH4, MeOH, rt; (b) MeONa, reflux; (c) EtONa, EtOH reflux; (d) Acetone, Na2CO3, reflux; (e) K3Fe(CN)6, 1%HCL/H2O, 90 °C; (f) 0.1 N NaOH aq, ROH; (g) R1NHR2, CH3CN.

The presence of the imine bond in the structure of sanguinarine makes it alkaline and hydrophilic, which enables it to react with the acidic components in the bacterial cell wall and interact with the lipid components in the cell membrane, thereby destroying the integrity and permeability of the bacterial cell wall and cell membrane and ultimately leading to bacterial cell lysis and death, thus realizing the antimicrobial effect (Gu et al., 2023). (Zhang et al., 2020) detected the changes of extracellular AKP and ions such as Na⁺, K⁺, Ca²⁺, and Mg²⁺, as well as intracellular ATP, pHin, cell membrane potential, and cellular morphology, and found that sanguinarine could achieve the inhibitory effect by destroying the integrity of the bacterial cell walls and cell membranes, and the imine bond in its structure played a key role. (Liu et al., 2022b) investigated the antimicrobial activity and mechanism of action of compounds 45 and 47 and found that 6-ethoxy and 7,8-methylenedioxy modifications enhanced the antimicrobial activity against MRSA. The MIC₂₀, MIC₅₀ and MIC₉₀ of compounds 45 and 47 against MRSA were 0.5/1/2, 0.5/1/4 µg/mL, respectively, which were stronger than that of sanguinarine. Mechanistic studies suggest that compound 45 may inhibit bacterial growth by targeting bacterial cell membranes and FtsZ. Compound 45 was found to interact with amino acid residues ILE164, ASN166, ALA186, ASP187, GLY22, and IAR10 in the FtsZ protein through hydrogen bonding and electrostatic interactions by molecular docking technique. 6-ethoxy and 7,8-methylenedioxygen in the structure positively affects the increase in membrane permeability and ROS generation, which enhances the antimicrobial activity of the compound. (Lv et al., 2018) synthesized derivatives with different substituents at the C-6 position from sanguinarine starting material, and in vitro antifungal assays showed that the synthesized derivatives showed EC₅₀ values between 1.0 and 4.4 µg/mL against Rhizoctonia solani, while sanguinarine showed an EC₅₀ value of 11.6 µg/mL, and showed moderate to low activity. The substitution of sanguinarine bases at N, C-6, C-7, and C-8 positions increased their potency against Rhizoctonia solani several-fold, with compounds 53 and 54 (Fig. 8) showing better biological activity and could be used as leading structures for further design of agricultural fungicides.

We were surprised to discover that modification of N atoms, including N atom quaternization, hydrogenation, alkylation, and benzylation, were involved in modification of all three alkaloids when we compared the modification sites as well as modification groups of simple isoquinolines, protoberberberines, and benzophenanthridines. It can be seen that the N atom plays a key role in the structure of isoquinoline alkaloids, which may be related to the special properties of the N atom, which can act as a hydrogen-bonding acceptor and form hydrogen-bonding interactions with hydrogen-bonding donors (e.g., hydroxyl groups, amino groups, etc.), thus affecting the conformation and interactions of the molecule; N atoms can be charged so as to have ionic bonding interactions with other oppositely charged substances, and such ionic bonding interactions are important for the binding of drugs to receptors, enzyme catalysis, etc.; N atoms can form covalent bonds by forming covalent bonds with other atoms, e.g., with C to form a C-N bond. The formation of these covalent bonds has an important effect on the stability and biological activity of molecules; The distribution of the electron cloud of N atoms has an important influence on the polarity and charge distribution of the molecule, which in turn affects the solubility of the molecule, drug metabolism, and other properties. Modification of simple isoquinoline and benzophenanthridine alkaloids involves not only the N atom, but also the isoquinoline parent nucleus, by introducing groups with different effects at different positions of the parent nucleus (e.g., fat-soluble groups such as alkyl, benzyl, etc.; water-soluble groups such as hydroxyl, amine, etc.; and groups that bind to a specific target, such as benzimidazole, which, due to its structural similarity to purine, is capable of competing with it to inhibit the synthesis of nucleic acids), and thus exhibits enhanced antimicrobial activity. The protoberberine alkaloids have fewer modifications at other positions in the parent nucleus except for modifications on the N atom of the parent nucleus, and the modifications mainly involve C-8, C-9, C-10, C-11, C-12, and C-13, with modifying groups similar to those of the other two classes of alkaloids. The modification sites, modifying groups, specific antimicrobial activities and possible mechanisms of various isoquinoline alkaloids are shown in Table 2.

Table 2 The modification sites, modification groups, the specific antibacterial activity, and possible mechanism of the various isoquinoline alkaloids.

Isoquinoline alkaloids	Modification sites and corresponding modifying groups	antimicrobial activity	possible mechanism
Simple Isoquinolines	C-1: Alkyl, benzyl, and other groups with high fat solubility. N: Alkyl, benzyl, N-atom quaternization, hydrogenation, etc.C-5: Halogen atom (F, Cl, Br) C-6,C-7: alkoxy, benzyloxy, methylenedioxy C-8: Hydroxyl, alkoxy and some fat-soluble groups.	Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus, Erwinia carotovora, Bacillus subtilis, Salmonella enteritidis, Candida albicans, Mycobacterium tuberculosis, Mycobacterium avium Physalospora piricola	FtsZ protein, ATP synthase, MurE ligase
Benzophenanthridines	N: N atom quaternized, hydrogenated C-6: keto, alkoxy, benzyl, carbonyl, amino, hydroxy C-7, C-8: methylenedioxy, alkoxy	Staphylococcus aureus, Escherichia coli, Aeromonas hydrophila, Pasteurella multocida, Rhizoctonia solani	DNA, antiapoptotic protein Bcl-XL, FtsZ protein, Cell wall, cell membrane, Biofilm

Isoquinoline alkaloids	Modification sites and corresponding modifying groups	antimicrobial activity	possible mechanism
Protoberberines	N: N atom quaternized, hydrogenatedC-8: keto, alkyl, halogen atoms (F, Cl, Br) C-9: alkoxy, benzyloxy, hydroxy, long-chain alkyl, and aromatic-substituted amino groups C-10, C-11: AlkoxyC-12: nitrogen-containing heterocycles (e.g., benzimidazolyl) C-13: alkyl, benzyl, ester group, amino group	Staphylococcus aureus, Helicobacter pylori, Bacillus subtilis, Salmonella enteritidis, Escherichia coli, Candida albicans, Candida tropicalis, Candida Lusitaniae, Candida Krusei, Shigella dysenteriae, Bacillus typhi	DNA, topoisomerase,urease (enzyme) , cell wall, Biofilms, cell membranes

3.4

3.4 Other categories

In addition to the simple isoquinolines, protoberberberines and benzophenanthridine isoquinoline alkaloids, there are also aporphines and benzylisoquinolines in this class. Three proaporphine alkaloids, litsericinone, 8,9,11,12-tetrahydromecambrine, Hexahydro-mescaline A, extracted from the leaves of Phoebe grandis (Nees) Merr. (Lauraceae), in vitro antimicrobial assay revealed that the three proaporphine alkaloids possessed broad-spectrum antibacterial activity, and their overall Gram-positive inhibitory effect was stronger than that of streptomycin sulfate (Omar et al., 2013).In addition, Tetrandrine, a bisbenzylisoquinoline alkaloid extracted from the radix of Stephania tetrandra S. Moore., showed MIC values of 125–250 µg/mL against Staphylococcus aureus. Mechanistic studies have revealed that Tetrandrine may exhibit antimicrobial activity by inducing disruption of the bacterial cell wall and by direct binding to PGN(Lee et al., 2012). The antimicrobial activity of these alkaloids suggests that other classes of alkaloids in addition to simple isoquinolines, protoberberberines and benzophenanthridines have potential for development as antimicrobial agents. (Zhang et al., 2021) designed and synthesized a class of benzothiazolyl-5-methylphenanthridine derivatives, based on which a novel class of indolyl-5-methylphenanthridine derivatives were further designed and synthesized by optimizing the benzothiazolyl-5-methylphenanthridine nucleus, and their antibacterial activities targeting the bacterial cytosolic protein Fts Z were evaluated. The results showed that the indolyl-5-methylphenanthridine derivatives exhibited significantly increased activity against a variety of drug-resistant strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Among them, compound 55 (Fig. 9) showed excellent antibacterial activity against both methicillin-resistant S. aureus and clinically isolated S. aureus with MIC values of 2 µg/mL. Mechanistic studies revealed that compound 55 affected the biological function of FtsZ and prevented bacterial division by affecting FtsZ polymerization and aggregating them into messy knots, similar to other FtsZ inhibitors reported. (Lasák et al., 2018) prepared Schiff bases by condensation of suitable aromatic aldehydes and amines and then prepared isoquinoline derivatives based on the mechanism of reduction of Schiff bases by free radical cyclization, where the derivatives 56–60 with R₄ as benzyl group (Fig. 9) showed excellent antibacterial activity against Bacillus subtilis and Mycobacterium sp with MIC in single digit micromolar values. The constitutive relationships indicate the positive effect of the charged nitrogen atom in the structure and the benzyl group as R₄ substituent on the antibacterial activity of the compounds. (Liu et al., 2017) designed, synthesized and evaluated the antibacterial activity of 5-methylphenanthridine derivatives in vitro against various Gram-positive and negative bacteria, where compounds 61–66 (Fig. 9) showed MIC values of 4 µg/mL against both Bacillus subtilis ATCC9372 and Streptococcus pyogenes, with twice the activity of sanguinarine. (Yoshida et al., 1999) A new derivative of 5-benzyloxyisoquinoline was synthesized using 5-hydroxyisoquinoline as the initial material. In vitro experiments showed that compound 67 (Fig. 9) containing 3-acetylamino-2-dichlorobenzyloxy had strong activity against Helicobacter pylori with a MIC of 0.025–0.05 µg/mL, but had no effect on a series of common gram-positive and gram-negative bacteria. Its activity against Helicobacter pylori is better than that of amoxicillin (MIC = 0.025–0.1 µg/mL) and clarithromycin (MIC = 0.05–0.1 µg/mL).

Reagents and conditions: (a) Hydrocarbon bromide (R2 -Br), sodium hydride, N,N-dimethylformamide, 0 °C-r.t, 2 h, N2 protection; (b) 4-Aminophenylboronic acid pinacol ester, Tetrakis (triphenylphosphine) palladium, potassium carbonate, 1,4-dioxane, water, 101 °C reflux, 12 h, N2 protection; (c) 2-Bromobenzoic acid, thionyl chloride, 78 °C reflux, 2 h; (d) Triethylamine, dichloromethane, 0 °C-r.t, 6 h; (e) Iodomethane, sodium hydride, N,N-dimethylformamide, 0 °C-r.t, 4 h, N2 protection; (f) Palladium acetate, triphenylphosphine, sodium carbonate, dry N,N-dimethylformamide, 155 °C reflux, 7 h, N2 protection; (g) Diisobutylaluminium hydride, dry tetrahydrofuran, 10 °C, 4 h, N2 protection; (h) 2 M Hydrochloricacid, 30 min; (i) EtOH, reflux, 1 h; (j) NaBH4, EtOH, r.t, 2 h; (k) Bu3SnH, AIBN, toluene, 104–106 °C, 3–6 h, activated MnO2, r.t, 18 h; (l) HCl, dioxane, r.t; (m) 1.SOCl2, reflux, 2 h; 2. Phenylaniline, TEA, DCM, rt, 3 h; (n) NaH, DMF, 0 °C∼rt; (o) Pd(OAc)2, PPh3, Na2CO3, dry DMF, reflux, 5 h; (p) 1. DIBAL, −10 °C∼rt; 2. 2 M HCl, 20 min; (q) NaH, DMF; (r) NH2NH2, FeCl3, H2O-MeOH; (s) Ac2O, Py, DMAP, Ac2O, ClCH2CH2Cl; (t) pyrrolidine, EtOH.

Appropriate structural modification of isoquinoline alkaloids can expand the scope of application and increase the value of drugs by improving their activity, metabolism and toxicity, as well as their stability and controllability, which are all of great significance for drug development and clinical application.

4 Discussion

Currently, the pharmacological activity of isoquinoline alkaloids has been extensively studied, especially in terms of antibacterial activity, and the investigation of Structure-activity relationship is an important research direction, mainly involving the optimization of their structural modifications, and the following points affecting the biological activity of isoquinoline alkaloids were summarized by reviewing the literature (Fig. 10):

Major modification groups and modification positions of various isoquinoline alkaloids.

Lipophilic structures, the introduction of lipophilic groups from different sites can be considered. For example, compound 15 (Fig. 4) obtained by introducing lipophilic groups (e.g., halogen atoms, alkyl groups, etc.) into the C- 5, C- 8, and N-positions of the tetrahydroisoquinoline had a MIC value of 1.2 µg/mL against Mycobacterium tuberculosis. Compound 21 obtained by introducing an alkyl group at the C-8 position using berberine as the initial substance (Fig. 5), the bioavailability of compound 21 was 10.03%, which was much higher than that of dihydroberberine 2.65%, compound 22 obtained by introducing an alkoxy group at the C-9 position of berberine (Fig. 5).The chemical properties of the above compounds were queried by Swiss ADME software and it was found that all the above compounds showed significant improvement in their lipophilicity (Daina et al., 2014) values from 1.82 to 3.85, −3.32 to −1.63 and −3.32 to −2.72, respectively, and water solubility (Delaney, 2004) Log S (ESOL) values from −2.1 to −5.8, −5.25 to −8.05 and −5.25 to −5.02, respectively, and gastrointestinal absorption (Daina and Zoete, 2016) was improved to varying degrees. The increase in the inhibition potency of the compounds with the increase in lipophilicity could be attributed to the increase in lipid solubility of the compounds and their ability to pass through the lipid cell membrance, thus achieving better antibacterial effect.

The introduction of heterocycles into the isoquinoline core, the formation of derivatives by thickening certain heterocycles (such as benzimidazole, thiadiazole and aminothiazole) with the parent nucleus of tetrahydroisoquinoline. For example, compound 25 (Fig. 5) obtained by introducing a nitrogen-containing heterocyclic amino group at the C-9 position of cyclic berberine exhibited potent antimethicillin-resistant Staphylococcus aureus potency (MIC value of 2 µg/mL). A novel benzimidazole-based tetrahydroproberberine was synthesized by cyclization of tetrahydroproberberine with aldehyde and o-phenylenediamine, in which the derivative 39 (Fig. 7) substituted with 5-fluorobenzimidazole group at the C-12 position possessed a broad-spectrum antimicrobial activity, with MIC values of 4.4 µM, 17.4 µM, and 14.5 µM against Bacillus subtilis, Shigella dysenteriae and Bacillus typhi, respectively, which were significantly stronger than berberine (MIC values of 1147.3 µM, 1147.3 µM and 458.9 µM, respectively. Compound 55 (Fig. 9) obtained by introducing an indole group into the structure of benzothiazolyl-5-methylphenanthridine showed excellent antibacterial activity against both methicillin-resistant Staphylococcus aureus and clinical isolates of Staphylococcus aureus with MIC values of 2 µg/mL. The chemical properties of the above compounds were checked by Swiss ADME software, and it was found that the introduction of heterocycles did not have a significant effect on their lipid solubility and water solubility, so we believe that the enhancement of their inhibitory ability may be due to the competition between these heterocycles and some substances in the process of bacterial metabolism and division, and it was found in the literature, that benzimidazole derivatives are able to inhibit the synthesis of nucleic acids due to their structural similarity to purines, thus inhibiting or even killing microorganisms(Fang et al., 2016; Zhang et al., 2016). By introducing heterocycles in addition to having steric interactions, they can also form donor–acceptor interactions with biological binding sites all of which may affect the antibacterial activity of the compounds.

The state of the N atom in isoquinolines has a large influence on their antimicrobial activity. As isoquinoline derivatives were synthesized from dopamine by Pictet-Spengler reaction, the results of in vitro antimicrobial experiments revealed that N-quaternization/alkylation is important to enhance the antimicrobial activity, among which compound 6 (Fig. 3) showed the highest inhibitory activity against all tested strains and inhibited Gram-positive bacteria better than gram-negative ones, with MIC values of 3.9 µg/mL against Staphylococcus aureus, Bacillus subtilis, Staphylococcus epidermidi, Candida albicans with MIC values of 3.9 µg/mL, and 15.6 µg/mL against Escherichia coli. The synthesized N-methyl tetrahydroproprotoberines29, 30 (Fig. 5), based on protopines, in vitro antimicrobial experiments showed that the positively charged N atom in the molecule positively influenced the antimicrobial effect, where the compounds 29, 30 against Staphylococcus aureus, Staphylococcus Gallinarum and Escherichia coli with MIC values of 250/125/62 µg/mL, 31.25/31.25/250 µg/mL, respectively. It has been shown that quaternary isoquinoline alkaloids have stronger bacterial inhibitory activity than tert-isoquinoline alkaloids, with the former showing a 3 to 3.5fold higher inhibition of NA than the latter (Cao et al., 2016), the subsequent analysis of enzyme inhibition kinetics and molecular simulations revealed that quaternary isoquinoline alkaloids (positively charged) can exert inhibition on neuraminidase protein (NA) through reversible receptor-ligand non-competitive behavior (Kim et al., 2014). It has also been reported that berberine reduces the thermal properties and the synergistic phospholipid phase transition of negatively charged DMPG bilayer, but not the amphoteric DMPC bilayer, because the electrostatic interaction between the positively charged nitrogen and the negatively charged lipid head group in berberine affects the function of the cell membrane, thus exhibiting an inhibitory effect on bacterial growth (G?Siorowska et al., 2011).

Joint modification at different locations, Combined modifications at multiple positions in the isoquinoline parent nucleus structure exhibit greater advantages than modifications at a single position. In addition, the substitution of N atoms in the structure may have an effect on the biological activity and solubility, and the number of oxygen bridges in the structure may also have an effect on the inhibition activity (Li and Zuo, 2010; Li Z et al., 1999).

Although the properties of isoquinoline alkaloids can be improved by appropriate structural modifications, some limitations and challenges may exist at the same time. Such as structural stability: the structures of isoquinoline alkaloids present in nature usually have a certain degree of stability, and certain positions or groups in their structures are not easy to be chemically reacted, this will greatly limit our selectivity and effectiveness in structural modification of isoquinoline alkaloids. Toxic side effects: The effects of structural modification of drugs are not accurately predictable and may enhance the therapeutic efficacy of the drug, but may also lead to increased toxicity or other side effects. This is because changes in the chemical bonding of the drug molecule or the introduction of new groups after structural modification may affect the physicochemical properties of the drug molecule (e.g., hydrophilicity, lipophilicity, metabolic pathways, etc.), thereby affecting the interaction between the drug and the organism. Structure-activity relationship: Structure modification may enhance or reduce the biological activity of a drug, but it may also completely destroy its activity. Therefore, before structural modification, it is necessary to comprehensively consider and predict the effects of different groups or functional groups on the activity of the molecule, and carry out reasonable optimization before modification; another point to consider is the ease of synthesis and cost. Overall, the structural modification of isoquinoline alkaloids is a challenging but at the same time promising task, which requires comprehensive consideration and analysis of the physicochemical properties of the drug molecules in order to ultimately achieve our desired results.

By summarizing the previous literature on structural modifications of isoquinolines, here we present the following ten protoberberine isoquinolines (all compounds not reported in PubChem compound database) (Fig. 11)with potential antibacterial activity based on the above summarized approach, and compare their binding ability with Filamenting temperature-sensitive mutant Z protein by moleculardocking simulation.

Predicted protoberberine type isoquinolines 1–10.

Filamenting temperature-sensitive mutant Z (Fts Z), a protein associated with cell division, is highly conserved in almost all bacterial species (40%-50% sequence homology) and plays an important role in the process of bacterial cell division, as Fts Z is depleted in the organism, cells gradually form long strips and eventually lyse and die (Sun et al., 2014). The nature of Fts Z in bacterial cell division was first demonstrated in Escherichia coli in 1991 (Dai and Lutkenhaus, 1991). By forming a Z-loop through the assembly of Fts Z monomers (Bi and Lutkenhaus, 1991; Oliva et al., 2004), the Z-loop determines the site of division and attracts other division-associated proteins after formation, and subsequent divisions can be completed in a stepwise manner through the coordinated action of daughter cells(Adams and Errington, 2009; Margolin, 2005). Numerous studies have shown that inhibition of bacterial division can be achieved by regulating Fts Z assembly and organizing the formation of ring-like structures. The mechanism of Fts Z assembly and Z-loop formation involves GTP binding and hydrolysis, regulated by the interaction of the N-terminal binding domain of one Fts Z monomer with the C-terminal GTPase-activating structural domain (C-terminal inter-domain cleft formed by β-sheet, T7-loop and H7-helic) (Fig. 12) on adjacent Fts Z monomers (Scheffers et al., 2002). Many small molecule inhibitors of Fts Z, such as berberine, have been shown to impede Fts Z polymerization and inhibit bacterial cell division (Beuria et al., 2005; Czaplewski et al., 2009; Domadia et al., 2007; Haydon et al., 2008; Huang et al., 2006; Ito et al., 2006; Plaza et al., 2010 ), berberine affects the GTPase activity of Fts Z by binding to the cleft between the C-terminal structural domains of Fts Z, ultimately achieving inhibition of bacterial division. The X-ray crystal structure of S. aureus Fts Z selected for this paper was retrieved from the RCSB Protein Data Bank (https://www.rcsb.org) (PDB code: 4DXD), and the water molecules, eutectic ligand PC190723 and GDP present in the structure were removed before docking. All compounds were constructed using the ChemDraw editor, converted to 3D structures and energy minimized, with the docking region on the C-terminal inter-domain cleft of Fts Z, and the optimal results were selected and checked by heavy atomic root-mean-square deviation (RMSD).

Fts Z protein (PDB code: 4DXD) C-terminal interdomain cleft (A) and its components (B).

Berberine binds to the Fts Z protein in the manner shown in Fig. 13ABC with a Bind-energy of −9.6 KCal/mol (1 KCal = 4.184 KJ) and interacts with the amino acid residues VAL297, THR265, THR309, LEU200, ILE197, GLY196, ILE311, GLY193 and MET226, and hydrogen bonding with amino acid residues GLY196 in the H7-helic structure and ASN263 and THR265 in the β-sheet structure. Among all the predicted compounds, compounds 4 and 5 had stronger cleavage binding ability to the C-terminal structural domain of Fts Z than berberine. Compound 4 Bind-energy was −11.5 KCal/mol and interacted with amino acid residues VAL203, VAL297, LEU209, LEU200, ASP199, ASN263, THR265, GLY196, THR309, ILE311, GLY193 and MET226 in the C-terminal structural domain of Fts Z. MET226, and hydrogen bonding with GLY196 in the H7-helic structure and ASN263 and THR265 amino acid residues in the β-sheet structure; Compound 5 Bind-energy was −10.4 KCal/mol, and there were interactions with amino acid residues VAL297, LEU200, GLY193, ASN263, THR265, ILE311, THR309, VAL307, GLY193, ILE228 and MET226 in the C-terminal structural interdomain cleft of Fts Z interaction and hydrogen bonding with amino acid residues GLY196 in the H7-helic structure and THR265 in the β-sheet structure; compounds 4 and 5 were bound to the C-terminal interdomain cleft of Fts Z in the manner shown in Fig. 13. The cleft binding pattern between the above compounds and the C-terminal structural domain of Fts Z protein revealed that the states of the N atom, C-8, C10-O and C9-O positions of the protoberberines isoquinoline were the key modification sites to improve the binding ability of this class of derivatives to Fts Z protein.

Surface diagram of berberine binding to C-terminal domain cleft (A), interaction with C-terminal domain cleft amino acid side chain (B) and hydrogen bond formation (C); Surface diagram of compound 4 binding to C-terminal domain cleft (D), interaction with C-terminal domain cleft amino acid side chain (E) and hydrogen bond formation (F); Compound 5 binding to C-terminal domain cleft (G), interaction with C-terminal domain cleft amino acid side chain (H) and hydrogen bond formation (I). (G), interaction with cleft amino acid side chains between C-terminal domains (H) and hydrogen bond formation (I).

Isoquinoline alkaloids are widely recognized as promising candidates for the development of novel antimicrobial drugs due to their broad-spectrum antimicrobial activity and their demonstrated efficacy against a wide range of drug-resistant strains. However, due to the diverse and complex microbiota of the human gastrointestinal tract, the mechanism of action of certain drugs is not well understood, leading to some controversy in some of the studies of drug activity, and drug design is still not fully predictable even today, making it possible to synthesize a target drug that was intended to be synthesized with unanticipated deviations. Therefore, the future structural modification of isoquinoline alkaloids requires more extensive research, such as expanding the type of biological activity screening: at this stage, the antimicrobial activity screening of isoquinoline alkaloids mainly focuses on the inhibitory activity against common pathogens, such as Pseudomonas aeruginosa and Staphylococcus aureus, etc. Further research can expand the screening targets to other drug-resistant strains and pathogenic microorganisms to expand the isoquinoline alkaloids' Antibacterial spectrum of isoquinoline alkaloids. Conducting clinical trials: assessing the clinical efficacy and safety of modified isoquinoline alkaloids as antimicrobial agents through a large number of experiments; developing suitable structural modification strategies for isoquinoline alkaloids to enhance antimicrobial activity, reduce toxicity and side effects, and optimize their drug properties. It is also necessary to obtain thorough conformational relationships to facilitate rational modification and transformation of isoquinoline alkaloids; a full understanding of the complex interactions between drugs and their hosts and the discovery of new potential targets are the keys to modern drug research. It is hoped that the summarization and conclusion of this paper can provide some reference for the development of new drugs related to isoquinoline alkaloids.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Introduction

Natural isoquinoline alkaloids and their antibacterial activity

Isoquinoline alkaloids structure modification methods

Structural modification of simple isoquinoline alkaloids
Structural modification of protoberberine alkaloids
Structural modifications of benzophenanthridine alkaloids
Other categories

Discussion

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No.	Compound	Structure	Antibacterial spectrum	MIC, IC₅₀ or inhibition circle diameter	Antibacterial target sites
2	Palmatine		Micrococcus lysodeikticus Bacillus cereus Bacillus megaterium Bacillus subtilis Staphylococcus aureus Staphylococcus epidermidis Escherichia coli Pemphigus vulgaris Salmonella enterica serovar typhi	(200 µg/mL) (Deng et al., 2012) (400 µg/mL) (300 µg/mL) (100 µg/mL) (200 µg/mL) (400 µg/mL) (800µg/mL) (600 µg/mL) (200 µg/mL)	DNA (Long et al., 2019) Topoisomerase (Deng et al., 2012) Neuraminidase (Kim et al., 2014) Urease (Zhou et al., 2017)
3	Coptisine		Helicobacter pylori Candida albicans	(25 µg/mL) (Li et al., 2018)(1000 µg/mL) (Kong et al., 2009)	Urease (Li et al., 2018) Cell wall, cell membrane (Iwasa et al., 1996) (Donlan and Costerton, 2002)

No.	Compound	Structure	Antibacterial spectrum	MIC, IC₅₀ or inhibition circle diameter	Antibacterial target sites
4	Chelerythrine		Staphylococcus aureus Methicillin-resistant Staphylococcus aureus Extended spectrum β-lactamases Staphylococcus aureus Marcescens Escherichia coli Candida albicans Cryptococcus neoformans	(156 µg/mL) (He et al., 2018) (156 µg/mL) (156 µg/mL)(125 µg/mL) (Qian et al., 2021)(0.0287 μM) (Wang Peiqing, 2013)(4 µg/mL) (Qian et al., 2020) (64 µg/mL)	FtsZ protein (Beuria et al., 2005) Cell wall, cell membrane (He et al., 2018) Biofilm (Qian et al., 2020)
5	Sanguinarine		Proteus rettgeri Rbapenem-resistant S. marcescens	(7.8 µg/mL) (Zhang et al., 2020)(32 µg/mL) (Fu et al., 2021)	Biofilm (Zhang et al., 2020) Cell Membrane (Fu et al., 2021) DNA (Shao et al., 2013)

No.	Compound	Structure	Antibacterial spectrum	MIC, IC₅₀ or inhibition circle diameter	Antibacterial target sites
6	Carnegine		Staphylococcus aureus Bacillus cereus Enterococcus faecalis Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Pemphigus vulgaris	(250 µg/mL) (Bouaziz et al., 2016) (500 µg/mL) (250 µg/mL) (125 µg/mL) (500 µg/mL) (250 µg/mL) (250 µg/mL)	–
7	N -methylisosalsoline		Staphylococcus aureus Bacillus cereus Enterococcus faecalis Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Pemphigus vulgaris	(400 µg/mL) (Bouaziz et al., 2016) (2000 µg/mL) (2000 µg/mL) (4000 µg/mL) (500 µg/mL) (4000 µg/mL) (4000 µg/mL)	–

No.	Compound	Structure	Antibacterial spectrum	MIC, IC₅₀ or inhibition circle diameter	Antibacterial target sites
8	(1′R,2′S)-coptichine B		Staphylococcus aureus Bacillus subtilis Escherichia coli Pseudomonas aeruginosa	(3.12 µg/mL) (Du et al., 2022) (3.12 µg/mL) (3.12 µg/mL) (3.12 µg/mL)	–
9	Berberidione		Staphylococcus aureus Bacillus subtilis Staphylococcus epidermidis Escherichia coli Klebsiella pneumoniae	(2 mg/mL,0.6 mL) (Alamzeb et al., 2015) (<25 mm) (<25 mm) (<25 mm) (<25 mm) (<20 mm)	–

No.	Compound	Structure	Antibacterial spectrum	MIC, IC₅₀ or inhibition circle diameter	Antibacterial target sites
10	Spathullin A		Staphylococcus aureus Escherichia coli Acinetobacter baumannii Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Candida albicans Aspergillus fumigatus	(4 µg/mL) (Nord et al., 2019) (15 µg/mL) (15 µg/mL) (15 µg/mL) (64 µg/mL) (64 µg/mL) (>64 µg/mL) (>64 µg/mL)	–
11	Spathullin B		Staphylococcus aureus Escherichia coli Acinetobacter baumannii Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Candida albicans Aspergillus fumigatus	(1 µg/mL) (Nord et al., 2019) (5 µg/mL) (5 µg/mL) (5 µg/mL) (32 µg/mL) (64 µg/mL) (>64 µg/mL) (>64 µg/mL)	–

Structural modification may be a way to make isoquinoline alkaloids efficient antibacterial drugs

Abstract

Keywords

Isoquinoline alkaloids

Antibacterial activity

Structural modification

Synthesis method

1 Introduction

2 Natural isoquinoline alkaloids and their antibacterial activity

3 Isoquinoline alkaloids structure modification methods

3.1 Structural modification of simple isoquinoline alkaloids

3.2 Structural modification of protoberberine alkaloids

3.3 Structural modifications of benzophenanthridine alkaloids

3.4 Other categories

4 Discussion

Declaration of Competing Interest

References

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