New heterocyclic benzoxazole-pyrrolidin-2-one derivatives: Synthesis, biological assessment, DFT and docking investigations

Abdulmalik S. A. Altamimi

doi:10.25259/AJC_183_2025

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Original Article

2025

:18;

1832025

doi:

10.25259/AJC_183_2025

New heterocyclic benzoxazole-pyrrolidin-2-one derivatives: Synthesis, biological assessment, DFT and docking investigations

Abdulmalik S. A. Altamimi^,*

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia

* Corresponding author: E-mail address: as.altamimi@psau.edu.sa (A.S.A. Altamimi)

Received: 2025-02-22, Accepted: 2025-04-12, Epub ahead of print: 2025-07-10, Published: 2025-07-23

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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

In this study, we synthesized new heterocyclic derivatives of pyrrolidinone linked to benzoxazole as part of an ongoing effort to combat the growing global threat of bacterial resistance. Antibiotic resistance, particularly against common pathogenic bacteria, has become a major challenge in public health, highlighting the urgent need for novel antimicrobial agents. The synthesized derivatives were obtained from 2-aminophenol and substituted amines. The structure of compounds 5-8 was confirmed using various analytical techniques, including ¹H, ¹³C, MS, and fourier transform infrared spectroscopy (FTIR) spectroscopy, which were consistent with the proposed structures. A brief density functional theory (DFT) theoretical study was conducted to explain the observed stability of derivatives 5-8, followed by a comparative analysis of theoretical and experimental NMR data. The antibacterial activity of the compounds was tested against four pathogenic bacterial strains, addressing the critical need for new agents with broad-spectrum efficacy. Finally, molecular docking studies were performed to explore the binding interactions and identify the most significant binding sites of the prepared ligands with biological targets. The calculated binding energy for derivative 8 is -8.54 kcal/mol, making it the best derivative due to its more significant interactions.

Keywords

Antibacterial activity

Bezoxazole moiety

DFT

Docking

Pyrrolidinone

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1. Introduction

The human organism is constantly under threat from a wide array of pathogens, including bacteria, viruses, and fungi. Among these, bacteria are particularly concerning due to their capacity to invade tissues and cause life-threatening infections. Gram-negative bacteria, such as E. coli [1], K. pneumoniae [2], P. aeruginosa [3], and A. baumannii [4], are especially problematic because they are implicated in severe health conditions, including pneumonia, urinary tract infections, meningitis, and sepsis. Similarly, Gram-positive bacteria like S. aureus and B. cereus are responsible for a variety of infectious diseases. S. aureus, which was associated with over a million deaths in 2019 [5,6], is known to cause conditions such as pneumonia, surgical site infections, neonatal mortality, and sepsis [7]. B. cereus, traditionally regarded as a pathogen in food and soil, has emerged as a cause of more severe infections, including endocarditis, respiratory diseases, and skin infections [8,9]. The growing issue of antibiotic resistance further complicates the treatment landscape. While antibiotics have been the primary method for managing bacterial infections, the rapid development of resistance, especially to third-generation antibiotics like carbapenems, has rendered many treatments ineffective. The emergence of these resistant strains presents a serious public health threat, leading the World Health Organization to prioritize research into combating antibiotic-resistant bacteria and to advocate for the development of novel treatment approaches [10,11].

Pyrrolidinones scafold is found in diverse active natural compounds. They have attracted more importance because of their applications in medicinal chemistry [12]. This molecule has shown a variety of therapeutic activities such as antibacterial [13], antimicrobial [14,15], analgesic [16], anticonsulvant [17], HIV-1 inhibitors [18], and as anticancer [19]. Therefore, diifent synthetic paths have been used for access to pyrrolidinones molecules [20-23].

On the other hand, benzoxazole moities have been attracted more attention of the scientist due to their therapeutic uses [24,25]. Actually, they have been known to show a prominent anti-cancer [26], anti-tumor [27], antimicrobial [28,29] and HIV-1 inhibitors [30] activities.

Small-molecule inhibitors targeting the essential prokaryotic cell division protein FtsZ have emerged as promising candidates for therapies, especially in the context of antibiotic-resistant infections [31]. However, no FtsZ inhibitors have yet advanced to clinical stages. Recently, a new series of substituted derivatives, specifically compounds A and B (Figure 1), were reported. These isoxazole derivatives showed significant improvements in both in vitro and in vivo models. Notably, the most remarkable enhancement was observed in their activity against the FtsZ G196A mutation, a common alteration associated with resistance to certain antibacterial agents, which makes S less effective [32].

Chemical structures of isoxazole and benzoxazole derivatives.

Recently, there has been significant interest in the development of heterocyclic scaffolds as potential antibacterial agents [33,34]. Among these, nitrogen-containing heterocyclic compounds have gained considerable attention from medicinal chemists. Benzimidazole derivatives are prominent within this group of potential therapeutic agents. They are recognized as a promising class of bioactive molecules, exhibiting a broad spectrum of activities, including antiprotozoal, anti-inflammatory, antihelminthic, antimalarial, antimicrobial, antiviral, antiparasitic, and antimycobacterial effects [35,36]. Additionally, benzoxazoles have garnered attention as key pharmacophores in synthetic and medicinal chemistry due to their significant pharmacological properties. This diverse family of compounds demonstrates a wide array of biological effects, such as anti-diabetic, anti-inflammatory, anticonvulsant, anticancer, antiviral, antibacterial, antituberculosis, antioxidant, and enzyme-inhibiting activities [37,38]. Figure 1 illustrates some commercially available drugs containing Benzoxazole derivatives, including examples like Flunoxaprofen and Tafamidis.

In continuation of our ongoing research projects focused on the development of biologically active heterocycles [39-42], this study aims to design and synthesize novel benzoxazole derivatives linked to 2-pyrrolidinones. These new compounds were carefully characterized and evaluated for their antibacterial activity, specifically against a range of pathogenic bacterial strains. In addition to the experimental antibacterial testing, computational studies, including Density Functional Theory (DFT) and molecular docking, were conducted to provide a deeper understanding of the interactions between the synthesized derivatives and potential bacterial targets. By combining experimental and computational approaches, we seek to identify promising candidates with enhanced antibacterial properties and offer insights into their mechanism of action, contributing to the development of new therapeutic agents in the fight against antibiotic-resistant bacterial infections.

2. Matrials and Methods

2.1. Chemistry

The NMR spectra were recorded using a Bruker 300 MHz spectrometer with DMSO-d6 as the solvent. The molecular mass of the products was determined by UPLC-MS (Q-TOF-ESI). The IR spectrum was obtained using a Shimadzu FT-IR spectrometer with KBr pellets.

2.1.1. Synthesis of derivatives 1-4

An equimolar mixture of the selected amines (45 mmol) and itaconic acid was dissolved in 30 mL of triple-distilled water and heated under reflux for approximately 45 mins. After the reaction mixture had cooled, it was filtered and washed with cold water. The obtained solid was then dissolved in a small amount of 10% aqueous NaOH then filter.

1-Methyl-5-oxopyrrolidine-3-carboxylic acid 1. Solid, yield 64 %, m.p. 151-153 °C. IR (KBr, cm^-1): 1672 (N-C=O), 1713 (HO-C=O), 2926 (Csp3-H), 3250 (COO-H). ¹H-NMR (δ, ppm): 2.59-2.78 (m, 2H, COCH₂), 3.61 (s, 3H, CH₃), 3.91-4.05 (m, 3H, NCH₂ & CH_pyrr), 11.32 (s, 1H, H_Acid); MS (m/z): 143.09 (M ^+.). calcd: C, 50.35; H, 6.34; N, 9.79. Found: C, 50.05; H, 6.40; N, 9.91.

1-Ethyl-5-oxopyrrolidine-3-carboxylic acid 2. Solid, yield 66 %, m.p. 156-158 °C. IR (KBr, cm^-1): 1665 (N-C=O), 1721 (HO-C=O), 2935 (Csp3-H), 3218 (COO-H). ¹H-NMR (δ, ppm): 1.40-1.44 (t, 3H, CH₃, J = 6 Hz); 2.59-2.79 (m, 2H, COCH₂), 3.57-3.72 (m, 2H, H₂C), 3.97-4.13 (m, 3H, NCH₂ & CH_pyrr), 11.39 (s, 1H, H_Acid); MS (m/z): 157.10 (M ^+.). calcd: C, 53.49; H, 7.05; N, 8.91. Found: C, 53.55; H, 7.12; N, 8.87.

1-Isopropyl-5-oxopyrrolidine-3-carboxylic acid 3. Solid, yield 68 %, m.p. 160-162 °C. IR (KBr, cm^-1): 1652 (N-C=O), 1718 (HO-C=O), 2941 (Csp3-H), 3225 (COO-H). ¹H-NMR (δ, ppm): 1.29-1.33 (d, 6H, H₃C, J = 6.3 Hz), 2.60-2.82 (m, 2H, COCH₂), 3.56-3.75 (m, 1H, CH), 3.98-4.14 (m, 3H, H₂CN & CH_p), 11.34 (s, 1H, H_Acid); ESI-MS (m/z): 171.11 (M ^+.) (C₈H₁₃NO₃). calcd: C, 56.13; H, 7.65; N, 8.18. Found: C, 56.32; H, 7.42; N, 8.25.

1-Cyclohexyl-5-oxopyrrolidine-3-carboxylic acid 4. Solid, yield 72 %, m.p. 185-187 °C. IR (KBr, cm^-1): 1638 (N-C=O), 1741 (HO-C=O), 2945 (Csp3-H), 3235 (COO-H). ¹H-NMR (δ, ppm): 1.05-1.75 (m, 10H, H₂C), 2.62-2.77 (m, 2H, COCH₂), 3.61-3.77 (m, 1H, H-C), 4.05-4.19 (m, 3H, H₂C-N & CH_pyrr), 11.30 (s, 1H, H_Acid); MS (m/z): 211.14 (M ^+.) (C₁₁H₁₇NO₃). calcd: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.42; H, 7.98; N, 6.48.

2.1.2. Synthesis of derivatives 5-8

A mixture of the appropriate 1-(methyl/ethyl/isopropyl/cyclohexyl-substituted)-5-oxopyrrolidine-3-carboxylic acids (15 mmol), polyphosphoric acid (15 g), and 2-aminophenol (15 mmol) was heated to 165°C and stirred for 4h. A 25 mL solution of 5-10% Na₂CO₃ was then added, and the mixture was heated for an additional 10 mins. After this period, 100 mL of water was added, and the mixture was stirred at 25°C for 15 mins. The obtained mixture was purified by column chromatography using a hexane/ethyl acetate eluent.

4-(Benzo[d]oxazol-2-yl)-1-methylpyrrolidin-2-one 5. Solid, yield 45 %, m.p. 87-89°C. IR (KBr, cm^-1): 1390 (C-N), 1558 (C=C), 1622 (CN), 1702 (CO), 3081 (CH_Ar). ¹H-NMR (δ, ppm): 2.89-3.09 (m, 2H, H₂C-CO), 3.76 (s, 3H, H₃C), 4.00-4.07 (m, 1H, CH_pyrr), 4.16-4.32 (m, 2H, NCH₂), 7.55-7.58 (d, 2H, H-4 &-7_oxazole, 8.10-8.13 (t, 2H, H-5_/-6 _{of Benz}, J = 7.2 Hz); ¹³C-NMR (δ, ppm): 172.82, 168.12, 151.21, 142.52, 125.72, 124.44, 120.02, 111.36, 50.53, 41.15, 35.51, 29.16; MS (m/z): 216.11 (M ^+.). Calcd: C, 66.65; H, 5.59; N, 12.96. Found: C, 66.82; H, 5.48; N, 13.15.

4-(Benzo[d]oxazol-2-yl)-1-ethylpyrrolidin-2-one 6. Solid, yield 48 %, m.p. 99-101 °C. IR (KBr, cm^-1): 1392 (C-N), 1556 (C=C), 1620 (CN), 1705 (CO), 3088 (HC_Ar). ¹H-NMR (δ, ppm): 1.85 (d, 3H, H₃C), 2.87-3.19 (m, 2H, COCH₂), 4.14-4.19 (m, 2H, H₂C), 4.22-4.37 (m, 3H, NCH₂ & CH_pyrr), 7.79-7.82 (d, 2H, H_{4 & 7 of oxazole}), 7.94-7.99 (t, 2H, H-5/-6 _{of oxazole}, J = 7.5 Hz); ¹³C-NMR (δ, ppm) : 172.55, 168.46, 151.12, 142.65, 125.37, 124.60, 120.09, 111.15, 49.24, 43.74, 41.47, 29.44, 19.52; MS (m/z): 230.12 (M ^+.); Anal. calcd: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.95; H, 6.27; N, 12.36.

4-(Benzo[d]oxazol-2-yl)-1-isopropylpyrrolidin-2-one 7. Solid, yield 48 %, m.p. 94-96 °C. IR (KBr, cm^-1): 1385 (C-N), 1562 (C=C), 1618 (CN), 1704 (CO), 3078 (CH_Ar). ¹H-NMR (δ, ppm): 2.19 (d, 6H, H₃C), 2.91-3.10 (m, 2H, COCH₂), 3.97-4.07 (m, 1H, HC), 4.19-4.31 (m, 3H, NCH₂ and CH_pyrr), 7.80-7.79 (d, 2H, H-4/-7_{of oxazole}, J = 9 Hz), 8.12-8.17 (t, 2H, H-5/-6_{of oxazole}, J = 7.5 Hz). ¹³C-NMR (δ, ppm): 172.55, 168.46, 151.37, 142.95, 125.33, 124.58, 120.07, 111.26, 53.28, 47.14, 41.93, 29.81, 20.74; MS (m/z): 244.14 (M ^+.); Calcd: C, 68.83; H, 6.60; N, 11.47. Found: C, 69.11; H, 6.83; N, 11.68.

4-(Benzo[d]oxazol-2)cyclohexylpyrrolidinone 8. Solid, yield 55 %, m.p. 129-131 °C. IR (KBr, cm^-1): 1378 (C-N), 1570 (C=C), 1625 (CN), 1700 (CO), 3097 (CH_Ar). ¹H-NMR (δ, ppm): 1.08-1.76 (m, 10H, Cyclohexane), 2.71-2.81 (m, 2H, H₂C), 3.65-3.84 (m, 3H, NCH₂ & CH_pyrr), 3.96-3.95 (m, 1H, HC), 7.35-7.38 (m, 2H, H-4_/-7_{of oxazole}), 7.59-7.73 (m, 2H, H-5/-6_{of oxazole}). ¹³C-NMR (δ, ppm): 172.44, 168.39, 151.59, 142.91, 125.88, 124.73, 120.51, 111.48, 57.65, 48.38, 41.93, 29.87, 28.53, 26.18, 23.48; MS (m/z): 284.16 (M ^+.).Calcd: C, 71.81; H, 7.09; N, 9.85. Found: C, 72.10; H, 7.25; N, 9.90.

2.2. Theoretical details

The ground-state geometries of compounds 5-8 were optimized using the DFT method at the B3LYP/6-311++G(d,p) level. Frequency analyses were conducted to confirm that the optimized structures of 5-8 represent true minima [43]. These calculations were carried out in a solvent, employing the Polarizable Continuum Model (PCM) to account for solvent effects.

2.3. Docking studies

The docking of the synthesized compounds into the active site of tyrosyl-tRNA synthetase was performed using the PDB entry 1JIJ [44]. The docking simulations were carried out using the AutoDock software suite [45]. A detailed description of the molecular docking procedure can be found in the literature [46].

3. Result and Discussion

3.1. Chemistry

The intermediate compounds 1-4, namely 1-(methyl/ethyl/isopropyl/cyclohexyl)-pyrrolidin-2-one-3-carboxylic acids, were synthesized by the fusion of appropriate amines with methylidenesuccinic acid in water. The subsequent reaction of these carboxylic acids 1-4 with 2-aminophenol was carried out using polyphosphoric acid, resulting in improved yields and purity of the benzoxazole derivatives 5-8 (Scheme 1).

Scheme for intermediates 1-4 and target compounds 5-8 synthesis.

The prototype intermediate derivative 1 exhibited characteristic absorption peaks in its IR spectrum, with bands at 1672 cm^-1 (CO of the acid), 1714 cm^-1 (CO), and 3250 cm^-1 (O-H). In the ¹H-NMR spectrum of derivative 1, the methyl protons appeared as a singlet at δ 3.59. The multiplets between δ 2.61 and 2.78 corresponded to two COCH₂ protons, while the range δ 3.91-4.05 represented two H₂C-N protons and one CH proton from the pyrrolidine ring. A singlet at δ 11.32 was assigned to the acid proton, which was confirmed to be exchangeable with D₂O. The final prototype compound 5 displayed specific IR absorption bands at 1622 cm^-1 (CN) and 1702 cm^-1 (CO). In the ¹H-NMR spectrum, the methyl protons appeared as a singlet at δ 3.77. The two COCH₂ protons from the pyrrolidine ring were identified as a multiplet in the range δ 2.93-3.09. Multiplets at δ 3.99-4.09 and δ 4.16-4.32 were assigned to one H-C proton and two H₂C-N protons of the pyrrolidine ring, respectively. The doublet at δ 7.54-7.57 was attributed to the H-4 and H-7 protons of the benzoxazole ring (J = 8.1). The other two protons of the benzoxazole ring were observed as a triplet at δ 8.08-8.12 (J = 7.2). The molecular ion (M⁺^.) peak of derivative 5 was detected at m/z 216.11, confirming its successful synthesis.

3.2. NMR elucidation

NMR prediction consists a power tool to validate the observed chemical shifts. The experimental chemical shifts of 5-8 along with their predicted ones are displayed in Table 1. Figures 2 and 3 represent the optimized structures of 5-8 and the correlation curves obtained for compound 1 between the experimental and the predicted values. The correlations curves between the predicted NMR chemical shifts of 5-6 and their corresponding experimental ones are relatively well reproduced with correlation coefficients higher than 98%. For ¹H, among 5-8, a minimal deviation is of 0.03 ppm obtained for 6, while a maximal deviation of 0.76 is obtained for 3 (Table 1). For ¹³C-NMR, among 5-8, a minimal deviation of 2.54 is obtained for 7, while a maximal deviation of 17 ppm is obtained for 8 (Table 1).

Table 1. Experimental and predicted (¹H & ¹³C)-NMR chemical shifts (ppm) for final products 5-8.

	5		\|Δδ\|	6		\|Δδ\|	7		\|Δδ\|	8		\|Δδ\|
	δ_Pred	δ_Exp	\|Δδ\|	δ_Pred	δ_Exp	\|Δδ\|	δ_Pred	δ_Exp	\|Δδ\|	δ_Pred	δ_Exp	\|Δδ\|
¹H-NMR
H2	2.96	3.01	0.05	3.11	3.03	0.08	3.20	3.00	0.20	2.66	2.7	0.04
H3	4.42	4.04	0.38	4.42	4.29	0.13	4.20	4.26	0.06	3.70	3.75	0.05
H4	3.80	4.24	0.44	4.15	4.29	0.14	4.52	4.26	0.26	3.55	3.75	0.20
H7	8.00	8.1	0.10	8.05	7.97	0.08	8.03	8.15	0.12	7.74	7.68	0.06
H8	7.70	7.56	0.14	7.76	7.8	0.04	7.74	7.81	0.07	7.44	7.37	0.07
H9	7.70	7.56	0.14	7.75	7.8	0.05	7.74	7.81	0.07	7.43	7.37	0.06
H10	7.86	8.1	0.24	7.92	7.97	0.05	7.90	8.15	0.25	7.60	7.68	0.08
H12	3.94	3.77	0.17	4.27	4.17	0.10	4.79	4.03	0.76	3.91	3.95	0.04
H13	-	-	-	1.75	1.85	0.10	1.89	2.20	0.31	1.39	1.3	0.09
H14	-	-	-	-	-	-	1.85	2.20	0.35	1.37	1.27	0.10
H15	-	-	-	-	-	-	-	-	-	1.50	1.53	0.03
H16	-	-	-	-	-	-	-	-	-	1.35	1.08	0.27
H17	-	-	-	-	-	-	-	-	-	1.50	1.74	0.24
¹³C-NMR
1	181.9	172.82	9.05	179.62	172.55	7.07	180.3	172.55	7.74	185.9	172.44	13.49
2	50.2	41.15	9.01	49.93	43.74	6.19	50.5	41.93	8.60	52.1	41.93	10.14
3	45.4	35.51	9.89	44.95	29.44	15.51	45.7	29.81	15.87	47.3	29.87	17.47
4	62.4	50.53	11.91	59.01	49.24	9.77	55.0	47.14	7.82	57.7	48.38	9.35
5	177.9	168.12	9.75	175.97	168.64	7.33	177.0	168.46	8.53	182.3	168.39	13.93
6	152.3	142.52	9.83	150.64	142.65	7.99	151.5	142.95	8.51	156.0	142.91	13.12
7	130.5	120.02	10.48	128.99	120.09	8.90	129.7	120.07	9.62	133.6	120.51	13.09
8	135.4	124.44	10.91	133.80	124.60	9.20	134.5	124.58	9.95	138.6	124.73	13.85
9	135.9	125.72	10.17	134.31	125.37	8.94	135.0	125.33	9.70	139.1	125.88	13.22
10	121.1	111.36	9.76	119.74	111.15	8.59	120.4	111.26	9.12	124.0	111.48	12.54
11	162.4	151.21	11.19	160.48	151.12	9.36	161.4	151.37	9.99	166.2	151.59	14.60
12	38.8	29.16	9.60	48.50	41.47	7.03	55.8	53.28	2.54	64.5	57.65	6.87
13	-	-	-	23.27	19.52	3.75	29.4	20.74	8.65	43.1	28.53	14.59
14	-	-	-	-	-	-	29.6	20.74	8.84	39.8	23.48	16.35
15	-	-	-	-	-	-	-	-	-	39.2	23.48	15.69
16	-	-	-	-	-	-	-	-	-	40.0	26.18	13.86
17	-	-	-	-	-	-	-	-	-	43.6	29.87	13.78

The optimized geometries of derivatives 5-8.

Predicted and experimental chemical shifts (a) 13C- and (b) 1H-NMR of product 5.

3.3. Antibacterial activity

The synthesized derivatives were subjected to antibacterial testing against several bacterial strains, which included two Gram-positive (GP) organisms (Methicillin-resistant Staphylococcus aureus and Bacillus subtilis) and Gram-negative (GN) species (Pseudomonas aeruginosa and Escherichia coli). The assessment was carried out according to a standardized protocol outlined in reference. The outcomes of the antibacterial tests are summarized in Table 2. Among the compounds investigated, derivatives 5-8 exhibited notable antimicrobial efficacy against all the bacterial strains, except for P. aeruginosa, where they showed no significant inhibitory effect. This indicates that these derivatives have promising antibacterial properties, especially against GP bacteria, but their activity against GN pathogens like P. aeruginosa may require further refinement to improve efficacy.

Table 2. Antibacterial activity of the derivatives 5-8.

			Bacterial Strains
			*Methicillin-resistant Staphylococcus aureus*	*Bacillus subtilis*	*P. aeruginosa*	*Escherichia coli*
Derivatives 5-8	5	MIC (μg/ml)	50	37.5	-	25
	6		50	37.5	-	25
	7		37.5	37.5	-	18.75
	8		10	11	-	13
	5	MBC (μg/ml)	37.5	25	-	18.75
	6		37.5	25	-	18.75
	7		25	25	-	12.5
	8		12.5	12.5	-	9.5
	5	Inhibition zone in mm (100 μg/ml)	7	9	-	12
	6		8	10	-	12
	7		10	11	-	13
	8		16	15	-	22
	5	IC₅₀ (µM)	231.48	173.61	-	115.74
	6		217.39	163.04	-	108.69
	7		153.68	153.68	-	76.84
	8		16	15	-	22
Ciproﬂoxacin		MIC (μg/ml)	18.75	12.5	12.5	12.5

3.4. Molecular docking

The antibacterial efficiency of prepared compounds 5-8 against methicillin-resistant staphylococcus aureus (MRSA) is displayed in Table 3. Compounds 5-7 showed moderate antibacterial activity, while 8 show potent activity. 5-7 differ slightly, in which the amine is substituted with methyl, ethyl and isopropyl alkyls, while in 4, the amine is substituted with cyclohexane. Then, the higher activity of 8 may relate to the cyclohexyl moiety.

Table 3. Docking of BEs, HBs and IC₅₀ values against MRSA.

Product	BEs (kcal/mol)	HBs	Residues interacted with ligand in the active site	IC₅₀ (µM) against MRSA
5	-6.02	1	PRO A53, CYS A37, GLY A38, HIS A50	231.48
6	-6.40	1	PRO A53, CYS A37, GLY A38, PHE A54, HIS A54	217.39
7	-6.82	1	PRO A53, CYS A37, GLY A193, GLY A38, TYR A36	153.68
8	-8.54	1	PRO A53, CYS A37, GLY A193, GLY A38, LEU A70	44.01

Table 3 presents an overview of the computed binding energies (BE) for the stable ligand-receptor complexes, along with the count of conventional intermolecular hydrogen bonds (HBs) formed between the docked compounds and the active site residues of the target enzyme. It also lists the specific amino acids involved in these interactions with the docked derivatives.

The interaction of the docked compounds 5-6 with the amino acids at the binding site of tyrosyl-tRNA synthetase results in negative bending energies, which could account for their significant antibacterial efficacy, as presented in Table 3. The molecular interactions between derivatives 5-8 and the tyrosyl-tRNA synthetase binding site are illustrated in Figure 4. In relation to the observed antibacterial potency, the superior activity of derivative 4 over derivatives 5-7 may be attributed to the enhanced stability of the complex between product 8 and tyrosyl-tRNA synthetase compared to the complexes formed with derivatives 5-7. A more negative binding energy indicates greater stability of the complex, which correlates with stronger binding affinity of the docked derivative within the active site of tyrosyl-tRNA synthetase (Table 3). The lone pairs on the nitrogen and oxygen atoms of benzo[d]oxazole in compounds 5-8 form hydrogen bonds with the CYS A37 residue of tyrosyl-tRNA synthetase at distances of 3.23, 3.00, 3.00, and 3.30 Å, respectively (Figure 4).

Interactions (2D & 3D) of derivatives 5-8 with tyrosyl-tRNA synthetase.

4. Conclusions

In Summary, the synthesis of novel benzoxale moiety linked to 2-pyrrolidinone derivatives was described using different available reactants. The final products 5-8 were tested for their antibacterial efficiency. All prepared compounds were found active against tested bacterial strains except Pseudomonas aeruginosa. In addition, molecular docking simulations were employed to investigate the binding interactions between the synthesized derivative and the target protein, tyrosyl-tRNA synthetase. The calculated binding energy for derivative 8 is -8.54 kcal/mol, making it the best derivative due to its more significant interactions. Moreover, a brief DFT theoretical study was carried out to explain the stability observed experimentally for derivatives 5-8, followed by a comparative analysis of theoretical and experimental NMR data which shows a significant correlation between the two studies.

Acknowledgement

This study is supported via funding from Prince Sattam bin Abdulaziz University project number (PSAU/2025/R/1446).

CRediT authorship contribution statement

Abdulmalik S. A. Altamimi: Conceptualization, Data curation, Methodology, Investigation, Methodology, Formal analysis, Validation, Writing - Original Draft. Writing - Review & Editing.

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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References

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1. Introduction

2. Matrials and Methods

2.1. Chemistry
2.2. Theoretical details
2.3. Docking studies

3. Result and Discussion

3.1. Chemistry
3.2. NMR elucidation
3.3. Antibacterial activity
3.4. Molecular docking

4. Conclusions

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[1] Peng Z., Wang X., Huang J., Li B.. Chapter 53 - Pathogenic Escherichia coli. In: Tang Y.-W., Hindiyeh M.Y., Liu D., Sails A., Spearman P., Zhang J.-R, eds. Molecular Medical Microbiology (3rd edition). Academic Press; 2024. p. :1065-1096.
[Google Scholar]

[2] Abbas R., Chakkour M., Zein El Dine H., Obaseki E.F., Obeid S.T., Jezzini A., Ghssein G., Ezzeddine Z.. General overview of Klebsiella pneumonia: Epidemiology and the role of siderophores in its pathogenicity. Biology. 2024;13:78. https://doi.org/10.3390/biology13020078
[Google Scholar]

[3] Qin S., Xiao W., Zhou C., Pu Q., Deng X., Lan L., Liang H., Song X., Wu M.. Pseudomonas aeruginosa: Pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics. Signal Transduction and Targeted Therapy. 2022;7:199. https://doi.org/10.1038/s41392-022-01056-1
[Google Scholar]

[4] Ahuatzin O.E., Torres E., Chavez E.. Acinetobacter baumannii, a multidrug-resistant opportunistic pathogen in new habitats: a systematic review. Microorganisms. 2024;12:644. https://doi.org/10.3390/microorganisms12040644
[Google Scholar]

[5] Wagenlehner F.M.E., Bjerklund Johansen T.E., Cai T., Koves B., Kranz J., Pilatz A., Tandogdu Z.. Epidemiology, definition and treatment of complicated urinary tract infections. Nature Reviews. Urology. 2020;17:586-600. https://doi.org/10.1038/s41585-020-0362-4
[Google Scholar]

[6] Ikuta K., Swetschinski L., Aguilar G., Sharara F., Mestrovic T., Gray A., Weaver N., Wool., Han C., Hayoon A., Aali A., Mekonen S., Abbasi M., Abbasi Z., Abd S., Abebe G., Abedi A., Abhari A.. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the global burden of disease study 2019. Lancet. 2022;400:2222-2248. https://doi.org/10.1016/S0140-6736(22)02185-7
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[7] Nwabuife J.C., Hassan D., Madhaorao Pant A., Devnarain N., Gafar M.A., Osman N., Rambharose S., Govender T.. Novel vancomycin free base – Sterosomes for combating diseases caused by staphylococcus aureus and methicillin-resistant staphylococcus aureus infections (S. aureus and MRSA) Journal of Drug Delivery Science and Technology. 2023;79:104089. https://doi.org/10.1016/j.jddst.2022.104089
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[8] Ehling-Schulz M., Lereclus D., Koehler T.M.. The bacillus cereus group: Bacillus species with pathogenic potential. Microbiology Spectrum. 2019;7:gpp3-0032. https://doi.org/10.1128/microbiolspec.GPP3-0032-2018
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[9] Butcher M., Puiu D., Romagnoli M., Carroll K.C., Salzberg S.L., Nauen D.W.. Rapidly fatal infection with Bacillus cereus/thuringiensis: Genome assembly of the responsible pathogen and consideration of possibly contributing toxins. Diagnostic Microbiology and Infectious Disease. 2021;101:115534. https://doi.org/10.1016/j.diagmicrobio.2021.115534
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[10] Minerdi D., Loqui D., Sabbatini P.. Monooxygenases and antibiotic resistance: A focus on carbapenems. Biology. 2023;12:1316. https://doi.org/10.3390/biology12101316
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[11] Koulenti D., Xu E., Mok I.Y.S., Song A., Karageorgopoulos D.E., Armaganidis A., Lipman J., Tsiodras S.. Novel Antibiotics for multidrug-resistant gram-positive microorganisms. Microorganisms. 2019;7:270. https://doi.org/10.3390/microorganisms7080270
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[12] Hosseinzadeh Z., Ramazani A., Hosseinzadeh K., Razzaghi-Asl N., Gouranlou F.. An overview on chemistry and biological importance of pyrrolidinone. Current Organic Synthesis. 2018;15:166-178. https://doi.org/10.2174/1570179414666170908165445
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[13] Gein V.L., Mihalev V.A., Kasimova N.N., Voronina E.V., Vakhrin M.I., Babushkina E.B.. Synthesis and antibacterial activity of 1-alkoxyalkyl-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones. Pharmaceutical Chemistry Journal. 2007;41:208-210. https://doi.org/10.1007/s11094-007-0047-9
[Google Scholar]

[14] Gein V.L., Armisheva M.N., Rassudikhina N.A., Vakhrin M.I., Voronina E.V.. Synthesis and antimicrobial activity of 1-(4-hydroxyphenyl)-4-acyl-5-aryl-3-hydroxy-3-pyrrolin-2-ones. Pharmaceutical Chemistry Journal. 2011;45 https://doi.org/10.1007/s11094-011-0584-0
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[15] Okumura K., Inoue I., Ikezaki M., Hayashi G., Nurimoto S., Shintomi K.. Synthesis and antiinflammatory activity of a series 1-aryl-2-pyrrolidinone derivatives. Journal of Medicinal Chemistry. 1966;9:315-319. https://doi.org/10.1021/jm00321a011
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[16] Gein V.L., Yushkov V.V., Kasimova N.N., Shuklina N.S., Vasil'eva M.Y., Gubanova M.V.. Synthesis and antiinflammatory and analgesic activity of 1-(2-aminoethyl)-5-aryl-4-acyl-3-hydroxy-3-pyrrolin-2-ones. Pharmaceutical Chemistry Journal. 2005;39:484-487. https://doi.org/10.1007/s11094-006-0006-x
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[17] Sasaki H., Mori Y., Nakamura J., Shibasaki J.. Synthesis and anticonvulsant activity of 1-acyl-2-pyrrolidinone derivatives. Journal of Medicinal Chemistry. 1991;34:628-633. https://doi.org/10.1021/jm00106a025
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[18] Ma K., Wang P., Fu W., Wan X., Zhou L., Chu Y., Ye D.. Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase. Bioorganic & Medicinal Chemistry Letters. 2011;21:6724-6727. https://doi.org/10.1016/j.bmcl.2011.09.054
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[21] Anada M., Hashimoto S.-ichi. Enantioselective synthesis of 4-substituted 2-pyrrolidinones by site-selective C-H insertion of α-methoxycarbonyl-α-diazoacetanilides catalyzed by dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate] Tetrahedron Letters. 1998;39:79-82. https://doi.org/10.1016/s0040-4039(97)10493-2
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[27] Cheng C.-C., Liu D.-F., Chou T.-C.. Design of antineoplastic agents on the basis of the 2-phenylnaphthalene-type’structural pattern. I: Synthesis of substituted 3-phenylquinazolones, benzoxazolo [2,3-b] quinazolones and benzothiazolo [2, 3-b] quinazolones. Heterocycles. 1993;35:775-789. https://doi.org/10.1021/jm00077a016
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[30] Hoffman J.M., Smith A.M., Rooney C.S., Fisher T.E., Wai J.S., Thomas C.M., Bamberger D.L., Barnes J.L., Williams T.M.. Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 4. 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one and analogs. Journal of Medicinal Chemistry. 1993;36:953-966. https://doi.org/10.1021/jm00060a002
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New heterocyclic benzoxazole-pyrrolidin-2-one derivatives: Synthesis, biological assessment, DFT and docking investigations

Abstract

Keywords

Antibacterial activity

Bezoxazole moiety

DFT

Docking

Pyrrolidinone

1. Introduction

2. Matrials and Methods

2.1. Chemistry

2.1.1. Synthesis of derivatives 1-4

2.1.2. Synthesis of derivatives 5-8

2.2. Theoretical details

2.3. Docking studies

3. Result and Discussion

3.1. Chemistry

3.2. NMR elucidation

3.3. Antibacterial activity

3.4. Molecular docking

4. Conclusions

Acknowledgement

CRediT authorship contribution statement

Declaration of competing interest

Declaration of Generative AI and AI-assisted technologies in the writing process

Supplementary data

References

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