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Novel 1,2,4-oxadiazole/pyrrolidine hybrids as DNA gyrase and topoisomerase IV inhibitors with potential antibacterial activity
⁎Corresponding authors at: Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China (Chunli Wu); Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt (Bahaa G. M. Youssif). bahaa.youssif@pharm.aun.edu.eg (Bahaa G.M. Youssif), bgyoussif@ju.edu.sa (Bahaa G.M. Youssif), wuchl@zzu.edu.cn (Chunli Wu) kedi2009@126.com (Chunli Wu)
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Received: ,
Accepted: ,
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
DNA gyrase is a promising target for antibacterial agents. Several classes of small-molecule inhibitors have been discovered in recent decades, but none of these have reached the market. We have designed a small library of 1,2,4-oxadiazole/pyrrolidine hybrids with mid nanomolar inhibitory and potent antibacterial activities against DNA gyrase and topoisomerase IV. Compounds 9, 15, 16, 19, and 21 inhibited Escherichia coli DNA gyrase to a similar extent as the reference compound, novobiocin, with inhibitory values ranging from 120 nM to 270 nM. Compound 16 was one of the most potent compounds in the series, with an IC50 value of 120 nM against E. coli gyrase, which is lower than the IC50 value of novobiocin (170 nM). Compound 16 had the highest inhibitory activity, with minimum inhibitory concentrations (MIC) of 24 and 62 ng/mL against Staphylococcus aureus and E. coli, respectively, which compared favorably with ciprofloxacin (30 and 60 ng/mL, respectively). Compounds 9, 15, 19, and 21 were similar to novobiocin in terms of their activity against E. coli and S. aureus topoisomerase IV, while compound 16 was more potent than novobiocin.
Keywords
1,2,4-Oxadiazole
Gyrase
Topoisomerase
Pyrrolidine
1 Introduction
Bacteria are microscopic single-celled organisms that are mostly harmless to humans and, in some cases, are beneficial (Cabeen and Jacobs-Wagner, 2010). However, some bacterial species are pathogenic and can lead to serious infections (Gao et al., 2018). Antibiotics are essential for treating bacterial infections, but due to antibiotic overuse and misuse, bacteria have developed resistance to nearly all antibiotics (Dhanda et al., 2019). Drug-resistant pathogens are estimated to cause approximately 700,000 deaths each year, and that number may rise to 10 million by the middle of the century if the current trend is maintained (Guo, 2019; Furst and Francis, 2019). As a result, drug-resistant pathogens have become a major threat to public health, necessitating the urgent development of more effective antibacterial drugs.
DNA topoisomerase enzymes are widely known as antibacterial targets because they induce changes in DNA topology, mediate the exchange between supercoiled and relaxed DNA, and are required for DNA duplication, transcription, and other cellular processes (Wang et al., 2019). Topoisomerases are classified into two groups based on their targets, despite their structural and mechanical differences. Topoisomerase I causes a transient break in one DNA strand, whereas topoisomerase II cuts both strands. Bacteria also have two enzymes, DNA gyrase and topoisomerase IV, that are structurally related to topoisomerase II (Aldred et al., 2014; Aldred et al., 2013). These enzymes play critical roles in DNA replication, transcription, and recombination. Consequently, inhibiting these enzymes is a critical goal for developing new antibacterial drugs and improving existing drugs (Collin et al., 2011).
Pyrrolidine is a five-membered heterocyclic moiety found in alkaloids such as nicotine (I) and hygrine (II) (Fig. 1) (Robertson et al., 2020; Shirsat et al., 2020). Several antimicrobial pyrrolidine derivatives have been described in the literatures (Arumugam et al., 2011; Bouton et al., 2018). Le Goffic demonstrated that the pyrrolidine moiety enhances the antibiotic activity of lincosamide antibiotics (Goffic et al., 1985). A series of methoxyquinoline derivatives linked with pyrrolidine show potent in vitro antibacterial activity against a variety of respiratory pathogens (Odagiri et al., 2013).
Structures of compounds I-VI and newly synthesized hybrids 8–23.
The oxadiazole moiety is a key structural motif in bioorganic and medicinal chemistry (Verma et al., 2021). There are four isomers of oxadiazole: 1,2,4-, 1,3,4-, 1,2,3-, and 1,2,5-oxadiazoles. The 1,3,4- and 1,2,4 oxadiazole isomers have received the most attention due to their higher metabolic stability than the other isomers (Dalvie et al., 2002). Researchers are interested in oxadiazole because of its potential as a therapeutic agent in a wide variety of medical applications, and because of its ease of preparation. Oxadiazole plays a significant role in the bioisosterism of esters and amides because it amends heir resistance to esterase-mediated hydrolytic cleavage (Zhang et al., 2013). Oxadiazole analog have a wide range of biological activities, including antimicrobial activity (Pidugu et al., 2016; Harish et al., 2013; Zheng et al., 2003; Guda et al., 2013; Rajak et al., 2013; Ahsan et al., 2012). The oxadiazole core requires special attention because it is found in many drug molecules, including oxolamine (III), prenoxdiazine (IV), butalamine (V), and fasiplon (VI), Fig. 1.
Despite the strong rationale for the development of new antibacterial drugs inhibiting DNA gyrase and topoisomerase IV, to the best of our knowledge, no reports describing the screening of 1,2,4-oxadiazole/pyrrolidine hybrids for DNA gyrase and topoisomerase IV inhibitory effects are available.
Molecular hybridization, in which two or more biologically active scaffolds are fused to produce novel agents against a desired drug target, is currently regarded as a promising approach (Mohassab et al., 2021; Abou-Zied et al., 2019; Abdelbaset et al., 2018). Based on these findings, and as part of our ongoing efforts to develop non-cytotoxic antibacterial agents (Hofny et al., 2021; Al-Wahaibi et al., 2021), we designed and synthesized a new series of 1,2,4-oxadiazole/pyrrolidine hybrids, (compounds 8–23, Fig. 1) using a molecular hybridization approach, and investigated their ability to inhibit Escherichia coli DNA gyrase. The most active compounds were then selected for further testing against Staphylococcus aureus DNA gyrase, and E. coli and S. aureus topoisomerase IV. The most active derivatives were assessed for their effects on cell viability and their antibacterial activity. Finally, molecular docking was used to predict the binding modes and interactions of the most active derivatives with DNA gyrase and topoisomerase IV.
2 Experimental
2.1 Chemistry
General Details: See Appendix A
Synthesis of the intermediates 2a-g (Karad et al., 2017), 3a-g (Ji et al., 2018), 5a-c and 6a-c (Ruan et al., 2020) according to reported procedures.
2.1.1 General synthesis of compounds 8–23
Compounds 7a-c and benzamidoxime 3a-g (1 mmol), EDC (1.2 mmol), and HOAt (1.1 mmol) were dissolved in DMF for 24 h at room temperature. Using triethylamine (1 mmol), the cyclodehydration was carried out by heating the reaction at 100 °C for 3–8 h. Following completion, 10 mL of water was added, and the mixture was extracted with EtOAc, washed several times with water and then with brine. The organic layers were dried over Na2SO4 and then evaporated under reduced pressure. Using silica gel column chromatography, the obtained products were purified and isolated as white solids in 25–50% yields.
2.1.1.1 (S)-N-(3-bromophenyl)-2-(3-(furan-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide (8)
Yield 30%; 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 7.98 (dd, J = 1.7, 0.6 Hz, 1H), 7.80 (t, J = 1.9 Hz, 1H), 7.47 (ddd, J = 8.2, 1.8, 1.0 Hz, 1H), 7.24 (dd, J = 3.5, 0.6 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 6.74 (dd, J = 3.5, 1.8 Hz, 1H), 5.29 (dd, J = 8.3, 3.2 Hz, 1H), 3.75 (dt, J = 9.3, 6.0 Hz, 1H), 3.63–3.56 (m, 1H), 2.38 (ddd, J = 14.9, 9.6, 5.5 Hz, 1H), 2.13–2.02 (m, 3H).13C NMR (101 MHz, DMSO) δ 181.43, 161.07, 153.98, 146.93, 142.13, 141.83, 130.80, 125.03, 122.11, 121.72, 118.61, 114.88, 112.75, 54.13, 46.85, 31.18, 24.86. HRESI-MS m/z calcd for [M + H]+ C17H16BrN4O3: 403.0406, found: 403.0400.
2.1.1.2 (S)-N-(3-bromophenyl)-2-(3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (9)
Yield 35%; 1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.88 (dd, J = 5.0, 1.2 Hz, 1H), 7.82–7.77 (m, 2H), 7.47 (ddd, J = 8.1, 1.8, 0.9 Hz, 1H), 7.26 (dd, J = 5.0, 3.7 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.12 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 5.30–5.26 (m, 1H), 3.76 (dt, J = 9.2, 6.0 Hz, 1H), 3.60 (dt, J = 9.2, 7.1 Hz, 2H), 2.44–2.35 (m, 1H), 2.13–2.02 (m, 4H). 13C NMR (101 MHz, DMSO) δ 181.49, 164.20, 154.01, 142.13, 131.25, 130.80, 130.45, 129.03, 127.79, 125.03, 122.11, 121.73, 118.61, 54.19, 46.89, 31.23, 24.89. HRESI-MS m/z calcd for [M + H]+ C17H16BrN4O2S: 419.0177, found: 419.0183
2.1.1.3 (S)-N-(3-bromophenyl)-2-(3-(5-(hydroxymethyl)furan-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide (10)
Yield 30%; 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 7.80 (t, J = 1.9 Hz, 1H), 7.49–7.46 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 5.6 Hz, 1H), 7.12 (ddd, J = 7.9, 1.6, 1.0 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 5.46 (t, J = 5.9 Hz, 1H), 5.28 (dd, J = 8.2, 3.1 Hz, 1H), 4.48 (d, J = 5.8 Hz, 2H), 3.80–3.71 (m, 1H), 3.59 (dd, J = 16.5, 7.1 Hz, 1H), 2.44–2.34 (m, 1H), 2.14–2.03 (m, 4H). 13C NMR (101 MHz, DMSO) δ 181.32, 161.07, 159.50, 153.97, 142.13, 140.92, 130.80, 125.03, 122.10, 121.72, 118.60, 115.56, 109.67, 56.09, 54.12, 46.85, 31.19, 24.87. HRESI-MS m/z calcd for [M + H]+ C18H18BrN4O4: 433.0511, found: 433.0500.
2.1.1.4 (S)-N-(4-chlorophenyl)-2-(3-(6-methoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (11)
Yield 25%; 1H NMR (400 MHz, DMSO) δ 7.94 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.39 (dd, J = 8.7, 2.4 Hz, 1H), 6.68 (d, J = 8.9 Hz, 2H), 6.44 (d, J = 8.9 Hz, 3H), 6.17 (d, J = 9.0 Hz, 1H), 4.48 (dd, J = 8.3, 3.2 Hz, 1H), 3.11 (s, 3H), 2.93 (dd, J = 10.7, 5.6 Hz, 1H), 2.77 (dd, J = 15.7, 8.0 Hz, 1H), 1.61–1.52 (m, 1H), 1.32–1.23 (m, 3H). 13C NMR (101 MHz, DMSO) δ 181.67, 166.22, 165.87, 154.14, 146.66, 139.42, 138.04, 128.89, 128.67, 126.14, 121.56, 119.53, 116.57, 111.87, 54.25, 46.86, 40.41, 40.20, 39.99, 39.79, 39.58, 34.43, 31.26, 24.88. HRESI-MS m/z calcd for [M + H]+ C19H19ClN5O3: 400.1176, found: 400.1175.
2.1.1.5 (S)-N-(4-chlorophenyl)-2-(3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (12)
Yield 30%; 1H NMR (400 MHz, DMSO) δ 8.86 (d, J = 6.0 Hz, 1H), 8.71 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.57 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 5,40 (t, J = 8.4 Hz, 1H), 3.83 (dt, J = 9.1, 6.1 Hz, 1H), 3.70–3.63 (m, 1H), 2.47 (td, J = 8.2, 4.4 Hz, 1H), 2.21–2.12 (m, 1H). 13C NMR (101 MHz, DMSO) δ 182.49, 166.79, 154.15, 151.39, 139.39, 133.87, 128.67, 126.17, 121.58, 121.43, 54.25, 46.87, 31.22, 24.89. HRESI-MS m/z calcd for [M + H]+ C18H17ClN5O2: 370.1071, found: 370.1062.
2.1.1.6 (S)-N-(4-chlorophenyl)-2-(3-(5-methylisoxazol-3-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (13)
Yield 30%; 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 0.7 Hz, 1H), 5.34 (dd, J = 7.9, 2.8 Hz, 1H), 3.76 (dt, J = 9.4, 6.0 Hz, 1H), 3.60 (dd, J = 16.4, 7.1 Hz, 1H), 2.51–2.50 (m, 1H), 2.41 (td, J = 8.2, 4.5 Hz, 1H), 2.10 (dd, J = 11.1, 6.2 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 182.59, 172.47, 161.38, 154.11, 152.66, 139.37, 128.67, 126.18, 121.60, 101.73, 54.16, 46.84, 31.16, 24.88, 12.29. . HRESI-MS m/z calcd for [M + H]+ C17H17ClN5O3: 374.1020, found: 374.1009.
2.1.1.7 (S)-N-(4-chlorophenyl)-2-(3-(furan-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide (14)
Yield 35%; 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.98 (d, J = 1.0 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 3.0 Hz, 1H), 6.74 (dd, J = 3.5, 1.8 Hz, 1H), 5.29 (dd, J = 8.2, 3.1 Hz, 1H), 3.75 (dt, J = 9.1, 5.9 Hz, 1H), 3.59 (dd, J = 16.5, 7.2 Hz, 1H), 2.38 (ddd, J = 15.2, 9.8, 5.7 Hz, 1H), 2.14–2.03 (m, 3H). 13C NMR (101 MHz, DMSO) δ 181.52, 161.06, 154.10, 146.91, 141.84, 139.41, 128.67, 126.15, 121.56, 114.86, 112.75, 54.10, 46.83, 31.18, 24.87. HRESI-MS m/z calcd for [M + H]+ C17H16ClN4O3: 359.0911, found: 359.0902.
2.1.1.8 (S)-N-(4-chlorophenyl)-2-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (15)
Yield 35%; 1H NMR (400 MHz, DMSO) δ 8.76–8.74 (m, 1H), 8.64 (s, 1H), 8.08–8.05 (m, 1H), 8.01 (td, J = 7.6, 1.7 Hz, 1H), 7.60 (ddd, J = 7.4, 4.8, 1.4 Hz, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 5,34 (t, J = 8.8 Hz, 1H), 3.81–3.75 (m, 1H), 3.64–3.58 (m, 1H), 2.41 (td, J = 8.2, 4.3 Hz, 1H), 2.15–2.07 (m, 3H). 13C NMR (101 MHz, DMSO) δ 181.96, 168.16, 154.11, 150.77, 146.11, 139.44, 138.18, 128.66, 126.57, 126.13, 123.80, 121.57, 54.19, 46.83, 31.23, 24.85. . HRESI-MS m/z calcd for [M + H]+ C18H17ClN5O2: 370.1071, found: 370.1061.
2.1.1.9 (S)-N-(4-chlorophenyl)-2-(3-(5-(hydroxymethyl)furan-2-yl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboxamide (16)
Yield 28%; 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 3.4 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 5.28 (dd, J = 8.3, 3.3 Hz, 1H), 4.49 (s, 2H), 3.75 (dt, J = 9.2, 6.0 Hz, 1H), 3.64–3.56 (m, 2H), 2.38 (ddd, J = 15.0, 9.7, 5.5 Hz, 1H), 2.12–2.03 (m, 3H). 13C NMR (101 MHz, DMSO) δ 181.41, 161.06, 159.49, 154.10, 140.93, 139.42, 128.67, 126.14, 121.55, 115.54, 109.66, 56.08, 54.09, 46.84, 31.19, 24.88. HRESI-MS m/z calcd for [M + H]+ C18H18ClN4O4: 389.1017, found: 389.1004.
2.1.1.10 (S)-N-(4-chlorophenyl)-2-(3-(thiophen-2-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (17)
Yield 30%; 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.88 (dd, J = 5.0, 1.2 Hz, 1H), 7.79 (dd, J = 3.7, 1.2 Hz, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 6.8 Hz, 2H), 7.26 (dd, J = 3.9, 2.6 Hz, 2H), 5.29 (dd, J = 8.2, 3.2 Hz, 1H), 3.80–3.73 (m, 1H), 3.60 (dd, J = 17.1, 7.7 Hz, 2H), 2.43–2.36 (m, 1H), 2.13–2.04 (m, 3H). 13C NMR (101 MHz, DMSO) δ 181.58, 164.19, 154.13, 139.41, 131.23, 130.44, 129.02, 128.67, 127.81, 126.15, 121.55, 54.16, 46.87, 31.23, 24.89. HRESI-MS m/z calcd for [M + H]+ C17H16ClN4O2S: 375.0682, found: 375.0673.
2.1.1.11 (S)-N-(4-chlorophenyl)-2-(3-(thiophen-3-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (18)
Yield 50%; 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 3.0, 1.2 Hz, 1H), 7.62 (dd, J = 5.1, 1.2 Hz, 1H), 7.42 (dd, J = 5.1, 3.0 Hz, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 8.9 Hz, 2H), 6.81 (s, 1H), 5.35 (dd, J = 7.7, 2.5 Hz, 1H), 3.74 (td, J = 8.2, 3.3 Hz, 1H), 3.67–3.60 (m, 1H), 2.45–2.29 (m, 4H), 2.24–2.16 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 179.23, 164.80, 153.58, 137.25, 128.91, 128.20, 127.94, 127.09, 126.07, 120.80, 53.70, 46.43, 30.87, 24.60. HRESI-MS m/z calcd for [M + H]+ C17H15ClN4O2S: 375.0682, found: 375.0663
2.1.1.12 (S)-2-(3-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)-N-(4-chlorophenyl)pyrrolidine-1-carboxamide (19)
Yield 45%; 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.62 (dd, J = 8.1, 1.2 Hz, 1H), 7.49 (d, J = 1.0 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 5.36–5.32 (m, 1H), 3.76–3.70 (m, 1H), 3.63 (dd, J = 15.7, 7.9 Hz, 1H), 2.43–2.26 (m, 3H), 2.24–2.10 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 179.37, 168.15, 162.65, 153.80, 150.37, 148.25, 137.49, 128.99, 128.26, 122.60, 120.98, 108.78, 107.62, 101.76, 77.16, 53.85, 46.56, 31.00, 29.83. HRESI-MS m/z calcd for [M + H]+ C20H18ClN4O4: 413.1017, found: 413.1014.
2.1.1.13 (S)-N-(4-iodophenyl)-2-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboxamide (20)
Yield 25%; 1H NMR (400 MHz, DMSO) δ 9.15 (d, J = 1.5 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.62 (s, 1H), 8.38–8.30 (m, 1H), 7.63–7.58 (m, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.9 Hz, 1H), 5,34 (t, J = 8.8 Hz, 1H), 3.77 (dt, J = 8.9, 6.0 Hz, 1H), 3.61 (dd, J = 16.5, 7.2 Hz, 1H), 2.44–2.37 (m, 1H), 2.15–2.07 (m, 3H). 13C NMR (101 MHz, DMSO) δ 182.09, 166.36, 154.08, 152.83, 148.16, 140.35, 137.40, 135.14, 124.83, 122.89, 122.31, 85.72, 54.24, 46.87, 31.24, 24.88. HRESI-MS m/z calcd for [M−H] + C18H15IN5O2: 460.0349, found: 460.2690.
2.1.1.14 (S)-2-(3-(5-(hydroxymethyl)furan-2-yl)-1,2,4-oxadiazol-5-yl)-N-(4-iodophenyl)pyrrolidine-1 carboxamide (21)
Yield 25%; 1H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 3.4 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 5,27 (t, J = 8.8 Hz, 1H), 4.49 (s, 1H), 3.75 (dt, J = 9.1, 5.9 Hz, 1H), 3.62–3.55 (m, 1H), 2.41–2.34 (m, 1H), 2.12–2.01 (m, 3H). 13C NMR (101 MHz, DMSO) δ 181.40, 161.06, 159.48, 154.02, 140.93, 140.36, 137.40, 122.29, 115.54, 109.67, 100.00, 85.70, 56.08, 54.09, 46.84, 31.19, 24.88. HRESI-MS m/z calcd for [M + H]+ C18H18IN4O4: 481.0373, found: 481.0363.
2.1.1.15 (S)-2-(3-(furan-2-yl)-1,2,4-oxadiazol-5-yl)-N-(4-iodophenyl)pyrrolidine-1-carboxamide (22)
Yield 45%; 1H NMR (400 MHz, DMSO) δ 8.60 (s, 1H), 7.98 (dd, J = 1.7, 0.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.23 (dd, J = 3.5, 0.6 Hz, 1H), 6.74 (dd, J = 3.5, 1.8 Hz, 1H), 5.28 (dd, J = 8.3, 3.2 Hz, 1H), 3.77–3.69 (m, 1H), 3.63–3.53 (m, 2H), 2.38 (ddd, J = 15.1, 9.8, 5.7 Hz, 1H), 2.13–1.98 (m, 4H). 13C NMR (101 MHz, DMSO) δ 181.50, 161.05, 154.02, 146.91, 141.83, 140.35, 137.40, 122.29, 114.86, 112.75, 85.71, 54.10, 46.83, 31.18, 24.86. HRESI-MS m/z calcd for [M + H]+ C17H16IN4O3: 451.0267, found: 451.0254
2.1.1.16 (S)-2-(3-(benzo[d][1,3]dioxol-5-yl)-1,2,4-oxadiazol-5-yl)-N-(4-iodophenyl)pyrrolidine-1-carboxamide (23)
Yield 25%; 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.1, 1.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.1 Hz, 1H), 6.85 (s, 1H), 6.04 (s, 2H), 5.33 (dd, J = 7.5, 2.7 Hz, 1H), 3.75–3.70 (m, 1H), 3.63 (dd, J = 15.8, 8.2 Hz, 1H), 2.45–2.26 (m, 3H), 2.19 (ddd, J = 12.1, 7.9, 3.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 179.27, 168.16, 153.64, 150.40, 148.27, 138.71, 137.91, 122.62, 121.57, 120.41, 108.80, 107.63, 101.78, 86.17, 53.83, 46.59, 29.84, 24.69. HRESI-MS m/z calcd for [M + H]+ C20H18IN4O4: 505.0373, found: 505.0368.
2.2 Biology
2.2.1 Determining the inhibitory activities against DNA gyrase and topoisomerase IV in E. coli and S. aureus
All compounds were assessed for inhibitory activity against DNA gyrase and topoisomerase IV using a supercoiling assay (Durcik et al., 2018), as described in Appendix A.
2.2.2 Minimum inhibitory concentration assay
Using a twofold serial dilution procedure (Swamy et al., 2011), the antibacterial activities of compounds 9, 15, 16, 19, and 21 were tested using ciprofloxacin as a reference compound, as described in Appendix A.
2.2.3 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay and cell viability
The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess the effect of compounds 8–23 on mammary epithelial (MCF-10A) cells (Abdelrahman et al., 2017; Elbastawesy et al., 2019), as described in Appendix A.
2.3 Docking experiment
Two-dimensional structures of compounds 9 and 16 were built using ChemDraw (PerkinElmer, Waltham, MA, USA). Protonated three-dimensional structures were then built with standard bond angles and lengths using Molecular Operating Environment 10.2008 software (MOE, 2008). Topoisomerase IV co-crystallized with a benzimidazole urea inhibitor. The structures of E. coli DNA gyrase B co-crystallized with a thiazole inhibitor were downloaded using Protein Data Bank (PDB) codes 3FV5 and 4DUH (Brvar et al., 2012; Wei et al., 2010).
3 Results and discussion
3.1 Chemistry
Scheme 1 describes the preparation of compounds 8–23. Aldehydes 1a–g were reacted in tetrahydrofuran with ammonia and iodine to yield the aryl nitriles 2a–g (Karad et al., 2017), which were then reacted with hydroxylamine in methanol to yield the amidoximes 3a–g (Ji et al., 2018). Isocyanates 5a–c were synthesized by stirring a solution of the anilines 4a–c, with triphosgene and triethylamine in dichloromethane (DCM) (Ruan et al., 2020). Et3N and compound 5 were stirred in DCM, with an appropriate amount of isocyanate, to produce the pyrrolidine-2-carboxylic acid esters 6a–c, which were then hydrolyzed with NaOH in methanol to produce the carboxylic acids 7a–c (Ruan et al., 2020).
Synthesis of compounds 8–23.
The oxadiazole-based derivatives 8–23 were synthesized by stirring the pyrrolidine-2-carboxylic acids 7a–c with the aryl amidoximes 3a–g in dimethylformamide in the presence of 1-hydroxy-7-azabenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide overnight. The solution was then heated at 100 °C for 3–8 h in the presence of triethylamine. Following extraction, column chromatography was used to purify the products to give compounds 8–23, with yields of 25–50%.
The 1H NMR spectrum of compound 16 showed the presence of a methylene signal due to the HO-CH2 group of the furan moiety, with an δ value of 4.49 (s) ppm, while the pyrrolidine proton signals gave δ values of 3.75 (dt, J = 9.2, 6.0 Hz, 1H), 3.64–3.56 (m, 2H), and 2.38 (ddd, J = 15.0, 9.7, 5.5 Hz, 1H); a multiplet of 3H at a δ value of 2.14–2.00; and characteristic signals of aromatic protons. The purity of the compound was confirmed by high-resolution electrospray ionization mass spectroscopy. These results were found to be consistent with the product’s molecular formula.
Reagent and reaction conditions: (i) NH3·THF, I, r.t 3 h, 80%; (ii) Hydroxylamine, NaHCO3, MeOH, r.t, 5 h, 90%; (iii) Triphosgene, DCM, 0 °C, Et3N, to r.t for 2 h; 80%; (iv) Et3N, DCM, r.t, 4 h to overnight 80%; (v) NaOH, methanol, r.t, overnight 90%; (vi) 1- EDCI, HOAT, r.t, DMF 24 h; 2- TEA,100 °C 3–8 h; 30–50%.
3.2 Pharmacological evaluation
3.2.1 Inhibitory activity against E. coli DNA gyrase
Supercoiling assay was used to test the compounds against E. coli DNA gyrase (Durcik et al., 2018). The results are given as residual enzyme activities (RAs) at 1 µM or as IC50 values for compounds having an RA lower than 50% (Table 1). Compounds 9, 15, 16, 19, and 21 inhibited E. coli DNA gyrase to a similar extend as to novobiocin (IC50 = 170 nM), with inhibitory values ranging from 120 to 270 nM. The p-chlorophenyl moiety was found in the backbones of three of the five most active compounds (15, 16, and 19; R1 = p-chlorophenyl; Table 1).
Compound
R1
R2
IC50 (nM)a or RA (%) b
E. coli DNA gyrase
8
3-bromo-
69%
9
3-bromo-
180 ± 20 nM
10
3-bromo-
310 ± 30 nM
11
4-chloro-
74%
12
4-chloro-
295 ± 50 nM
13
4-chloro-
84%
14
4-chloro-
57%
15
4-chloro-
210 ± 20 nM
16
4-chloro-
120 ± 10 nM
17
4-chloro-
89%
18
4-chloro-
100%
19
4-chloro-
250 ± 20 nM
20
4-iodo-
77%
21
4-iodo-
270 ± 20 nM
22
4-iodo-
89%
23
4-iodo-
480 ± 50 nM
Novobiocin
–
–
170 ± 20 nM
The 5-hydroxymethyl-furan-2-yl-1,2,4-oxadiazole derivative 16 (R1 = p chlorophenyl, R2 = 5-hydroxymethyl furan) was the most potent of all of the synthesized derivatives, with an IC50 value of 120 nM. It was more potent than the reference novobiocin (IC50 = 170 nM). When the p-chlorophenyl moiety in compound 16 was replaced with m-bromophenyl or p-iodophenyl, the IC50 values were reduced by at least 2.25-fold, as in compounds 10 (R1 = m-bromophenyl, R2 = 5-hydroxymethyl furan) and 21 (R1 = p-iodophenyl, R2 = 5-hydroxymethyl furan), indicating the importance of the p-chlorophenyl moiety for the inhibitory activity of the compounds.
The presence of o-pyridine or 1,3-benzodioxole moieties with a p-chlorophenyl core improved the potency of the compounds against DNA gyrase, as seen in compounds 15 (R1 = p-chlorophenyl, R2 = o-pyridine) and 19 (R1 = p-chlorophenyl, R2 = 1,3-benzodioxole) with IC50 values of 210 and 250 nM, respectively, while compounds containing other heterocycles, such as furan, thiophene, and oxazole within the same nucleus demonstrated a moderate level of activity, such as in compound 13 (R2 = 5-methyl oxazole), 14 (R2 = furan), and 17 (R2 = thiophene) with RA values of 84%, 57%, and 89%, respectively.
3.2.2 Inhibitory activity against S. aureus topoisomerase IV and DNA gyrase
Compounds with the lowest IC50 values were assessed against E. coli and S. aureus DNA gyrase and S. aureus topoisomerase IV (Durcik et al., 2018) (Table 2). Compounds 9, 16, and 19 were potential inhibitors of both E. coli and S. aureus DNA gyrase (Table 2). Compounds 9 and 16 had IC50 values in the sub-micromolar range against S. aureus DNA gyrase (IC50 = 0.82 and 0.21 µM, respectively), while compound 19 had an IC50 value of 2.49 µM. In all cases, compounds 9, 16, and 19 were less potent than novobiocin (IC50 = 0.041 µM).
Compound
IC50 (µM)a or RA (%) b
S. aureus gyrase
E. coli topoisomerase IV
S. aureus topoisomerase IV
9
0.82 ± 0.1 µM
12 ± 0.20 µM
23 ± 0.5 µM
15
1.7 ± 0.50 µM
54%
28.1 ± 1.5 µM
16
0.21 ± 0.02 µM
3.07 ± 0.06 µM
5.2 ± 0.2 µM
19
2.49 ± 0.90 µM
13.8 ± 1.20 µM
31.2 ± 1.8 µM
21
3.1 ± 1.2 µM
76%
33 ± 1.50 µM
Novobiocin
0.041 ± 0.07 µM
11 ± 2 µM
27 ± 2 µM
Against topoisomerase IV from E. coli and S. aureus, the activities of compounds 9, 15, 19, and 21 were similar to those of novobiocin. Compound 16 had IC50 values of 3.07 µM and 5.2 µM against E. coli and S. aureus topoisomerase IV, respectively, whereas novobiocin had lower potency against these two enzymes (IC50 = 11 µM and 27 µM, respectively). Compound 9 ranked second in efficiency, exhibiting moderate activity compared with all of the four enzymes evaluated, with an IC50 value of 23 µM against S. aureus topoisomerase IV (novobiocin IC50 = 27 µM). Therefore, hybrids 9 and 16 appeared to be potential dual-target inhibitors. Although compound 15 showed an IC50 = 28 µM against topoisomerase IV from S. aureus, compounds 15 and 21 did not have the same inhibitory effect on the other three enzymes as they did on E. coli DNA gyrase.
Therefore, our newly rationalized scaffold was highly effective at inhibiting topoisomerase IV and DNA gyrase. This is consistent with previous studies demonstrating that the oxadiazole moiety is an efficient pharmacophore that suppresses topoisomerase IV and DNA gyrase activity (Jakopin et al., 2017).
3.2.3 Minimal inhibitory concentration assay
Using ciprofloxacin as a reference compound and the twofold serial dilution procedure (Swamy et al., 2011), the antibacterial activities of compounds 9, 15, 16, 19, and 21 were evaluated. Overall, the evaluated compounds inhibited gram-negative bacteria less effectively than gram-positive bacteria, as shown in Table 3. The most potent antibacterial activity was demonstrated by compound 16, with a minimal inhibitory concentration (MIC) of 24 ng/mL against S. aureus, which is lower than the MIC of ciprofloxacin (30 ng/mL). However, an MIC of 62 ng/mL was demonstrated against E. coli, which is similar to that of ciprofloxacin (MIC = 60 ng/mL). Compound 9 showed comparable MICs to those of ciprofloxacin against the four evaluated species. Compounds 19 and 21 inhibited Bacillus subtilis with MICs of 79 and 68 ng/mL, respectively. However, the MICs of compounds 19 and 21 against Pseudomonas aeruginosa were > 100 ng/mL, and compound 15 exhibited no antibacterial activity against gram-negative bacterial strains.
Minimum inhibitory concentration (MIC) in /ml
Compound
Bacterial species
(G+)
(G-)
Bacillus subtilis
Staphylococcus aureus
Escherichia coli
Pseudomonas aeruginosa
9
17
30
65
70
15
60
52
>100
>100
16
12
24
62
65
19
79
35
82
>100
21
68
40
78
>100
Ciprofloxacin
10
30
60
60
3.2.4 Cell viability assay
The human mammary gland cell line MCF-10A was used to perform cell viability assays (Abdelrahman et al., 2017; Elbastawesy et al., 2019). Compounds 9, 15, 16, 19, and 21 were incubated with MCF-10A cells for 4 days, after which an MTT assay was used to assess cell viability. The tests revealed no cytotoxic effects, and the viability of the cells treated with the compounds exceeded 84% at 50 µM, as shown in Fig. 2.
Cell Viability assay of compounds 9, 15, 16, 19, and 21.
Based on these findings, compounds 9, 15, 16, 19, and 21 have potential as antibacterial drugs targeting topoisomerase IV and DNA gyrase, while having no cytotoxic effects on normal cells.
3.3 Molecular docking study
3.3.1 DNA gyrase B of E. coli
The binding patterns of the new compounds were evaluated through docking simulations of the E. coli DNA gyrase B active site to determine their capability of satisfying the features required for binding interactions.
Self-docking using the co-crystallized thiazole inhibitor was used to validate the docking setup (PDB ID: 4DUH) in the E. coli DNA gyrase B active site (Brvar et al., 2012). The docking protocol was appropriate for the docking study, with a root mean square deviation (RMSD) value of 0.888. Moreover, the essential interactions generated by the co-crystallized ligands in the active site were reproduced through the docking pose. The energy score of the docking was S = −13.13 kcal/mol. Through H-bonding, Arg76 and Arg136 interacted with Ph-COO-, while Arg76 interacted with the phenyl moiety via an arene–cation interaction. Lys103 interacted with the thiazole moiety through an arene–cation interaction. The Ph-NH function interacted with Lys101 through H-bonding. A water bridge facilitated the H-bonding of Thr165, Asp73, and Gly77 with the N3 of thiazole (Fig. 3, Table S1, Suppl. files). The docking energy scores of −14.79 and −12.36 kcal/mol for compounds 9 and 16, respectively, indicated that they may fit into the E. coli DNA gyrase B binding site. The most active compounds 9 and 16 engaged hydrophobically and formed hydrogen bonds with the critical amino acids Arg76 and Lys103, respectively. In compound 9, Arg76 interacted with the 1,2,4-oxadiazole ring via an arene–cation interaction. Further, Lys103 interacted with the thiophene ring via an arene–cation interaction, while Arg136 interacted with the N2 of the 1,2,4-oxadiazole ring via an H-bond. Gly101 interacted with the NH proton of the secondary amide CONHPh via H-bonding (Fig. 4, Table S1, Suppl. files). In compound 16, Arg76 interacted with the 1,2,4-oxadiazole ring through an arene–cation interaction. Moreover, Lys103 interacted with the furan ring via an arene–cation interaction, while Lys103 and Asn46 interacted with oxygen in the CH2OH group through H-bonding via a water bridge. His83 interacted with the benzene ring through an arene–cation interaction (Fig. 5, Table S1, Suppl. files). Additionally, hydrophobic interactions were observed between aryl, heteroaryl, and alkyl moieties and the amino acids lining the pocket for both compounds.
The docking of thiazole inhibitor into the DNA gyrase B active site of E. coli as a 3D diagram on the right, and a 2D diagram on the left, demonstrating its binding interactions.
The docking of Compound 9 in the DNA gyrase B active site of E. coli as a 3D diagram on the right and a 2D on the left, demonstrating the binding interactions.
The docking of Compound 16 in the DNA gyrase B active site of E. coli is shown as a 3D diagram on the right and a 2D diagram, demonstrating the binding interactions.
3.3.2 E. coli topoisomerase IV
The self-docking of the co-crystallized thiazole inhibitor in the active site of E. coli DNA topoisomerase was used to validate the docking setup (PDB ID: PDB code: 3FV5) (Wei et al.). The docking procedure was validated through self-docking, with an RMSD value of 1.07. The co-crystallized ligands in the active site were used to ensure that the docking pose had the capacity to regenerate the essential interactions. The docking energy score was S = -14.60 kcal/mol. Arg132 formed an H-bond with the N pyridine ring, and Arg72 interacted with the pyridine ring via an arene–cation interaction. A water bridge facilitated the interaction of Asn42 with acetyl oxygen through H-bonding. Gly73, Asp69, and Thr163 formed H-bonds with the N3 of benzimidazole via a water bridge. By H-bonding, Asp69 interacted with the N1H and NH3 of urea, and Ser43 interacted with the NH3 of urea (Fig. 6, Table S2, Suppl. files). The docking energy scores of 12.16 and −14.51 kcal/mol for compounds 9 and 16, respectively, indicated that they may fit into the E. coli DNA topoisomerase IV binding site. Compounds 9 and 16 formed hydrogen bonds and interacted hydrophobically with the essential amino acids of DNA topoisomerase. In compound 9, Arg132 interacted with the thiophene ring through an arene–cation interaction. Moreover, Arg72 interacted with the 1,2.4-oxadiazole ring through an arene–cation interaction. Asp69, Gly73, and Thr169 interacted via hydrogen bonding with carbonyl oxygen through a water bridge (Fig. 7, Table S2, Suppl. files). In compound 16, Ser43 interacted with CH2OH oxygen via H-bonding. Asp69 and Thr163 interacted with the CH2OH proton via H-bonding. Asp69, Gly73, and Thr163 interacted via H-bonding with the N2 of 1,2.4-oxadiazole through a water bridge (Fig. 8, Table S2, Suppl. files).
The benzimidazole-2-yl urea inhibitor docked into DNA topoisomerase IV active site of E. coli on the left. Also, a 3D diagram demonstrates its binding interactions on the right.
9 docked into the DNA topoisomerase IV active site of E. coli on the left. Also, a 3D diagram representation demonstrates its binding interactions on the right.
16 docked into the of E. the DNA topoisomerase IV active site of E. coli on the left. Also, a 3D diagram representation demonstrates its binding interactions on the right.
4 Conclusions
Sixteen compounds were developed, produced, and assessed for their activity against DNA gyrase and topoisomerase IV, and against many gram-negative and gram-positive bacterial strains. The most active compound in enzymatic testing was compound 16, which has a p-chlorophenyl substituent on the pyrrolidine moiety and a 5-hydroxymethyl furan on the 1,2,4-oxadiazole ring. Compound 16 showed an IC50 of 0.21 M against S. aureus DNA gyrase and 120 nM against E. coli DNA gyrase. Moreover, it showed activity against S. aureus topoisomerase IV (IC50 = 5.2 M) and E. coli topoisomerase IV (IC50 = 3.07 M). Compound 16 demonstrated excellent antimicrobial effects against gram-positive bacteria, with MIC values of 62 and 24 ng/mL against E. coli and S. aureus, respectively. Thus, compound 16 is a good starting point for future optimization, due to its low-micromolar MIC values against gram-positive bacteria, its low-nanomolar enzymatic activity against topoisomerase IV and DNA gyrase, and its low cytotoxicity.
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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Appendix A
Supplementary material
Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2021.103538.
Appendix A
Supplementary material
The following are the Supplementary data to this article:Supplementary data 1
Supplementary data 1
Supplementary data 2
Supplementary data 2
