Benzothiazole and 2,3-dihydro-1,5-benzoxazepine Derivatives Demonstrate Antimicrobial Activity: An Antimicrobial and ADMET Study

Abstract

Antimicrobial resistance continues to be a serious public health threat globally, hence the continuous design of new clinical candidates with novel mechanisms of action. Heterocyclic drugs have been a hotspot in antibiotic research. Benzothiazole and 2,3-dihydro-1,5-benzoxazepine are anticancer derivatives. To follow up on their antimicrobial activity, the current work resynthesized 13 benzothiazole, benzimidazole, benzothiazepine, and 2,3-dihydro-1,5-benzoxazepine derivatives, followed by the evaluation of their antimicrobial and antitubercular activity against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Klebsiella pneumonia, Bacillus subtilis, Streptococcus mutans, Salmonella typhi, and Mycobacterium tuberculosis. In addition, in silico ADMET studies were performed on the compounds using the ADMET Laboratory 2.0 platform. The compounds were found to be active against all the bacterial strains except against S. mutans and S. typhi. 4-[(E)-2-(2-chlorophenyl)ethenyl]-2,2-dimethyl-2,3-dihydro-1,5-benzoxazepine (3) was found to be the most active against E. coli, 2,2,4-trimethyl-2,3-dihydrobenzoxazepine (12) the most active against MRSA, and 4-[(E)-2-(4-methoxyphenyl)ethenyl]-2,2-dimethyl-2,3-dihydro-1,5-benzoxazepine (6) the most active against Klebsiella pneumoniae. The compounds also showed moderate activity against M. tuberculosis. The ADMET analysis predicted largely drug-like properties of the compounds and their suitability as potential drugs. The synthesized compounds showed good activity against some of the selected organisms and, therefore, could be modified to improve their action as antimicrobial agents.

Keywords

benzoxazepines - benzothiazole - anti-microbial - antitubercular - ADMET analysis

Publication History

Received: 10 January 2025

Accepted: 28 September 2025

Article published online:
07 November 2025

• References

• 1 Prescott JF. The resistance tsunami, antimicrobial stewardship, and the golden age of microbiology. Vet Microbiol 2014; 171 (3-4): 273-278
• 2 Bhardwaj S, Mehra P, Dhanjal DS. et al. Antibiotics and antibiotic resistance-flipsides of the same coin. Curr Pharm Des 2022; 28 (28) 2312-2329
• 3 Greenwood D. Antimicrobial Drugs: Chronicle of a Twentieth-Century Medical Triumph. Oxford: Oxford University Press; 2008
• 4 Salam MA, Al-Amin MY, Salam MT. et al. Antimicrobial resistance: a growing serious threat for global public health. Healthcare (Basel) 2023; 11 (13) 1946
• 5 Flynn CE, Guarner J. Emerging antimicrobial resistance. Mod Pathol 2023; 36 (09) 100249
• 6 Pipitò L, Rubino R, D'Agati G. et al. Antimicrobial resistance in ESKAPE pathogens: a retrospective epidemiological study at the University Hospital of Palermo, Italy. Antibiotics (Basel) 2025; 14 (02) 186
• 7 Singh A, Tanwar M, Singh TP, Sharma S, Sharma P. An escape from ESKAPE pathogens: a comprehensive review on current and emerging therapeutics against antibiotic resistance. Int J Biol Macromol 2024; 279 (Pt 3): 135253
• 8 Huttner B, Harbarth S, Nathwani D. ESCMID Study Group for Antibiotic Policies (ESGAP). Success stories of implementation of antimicrobial stewardship: a narrative review. Clin Microbiol Infect 2014; 20 (10) 954-962
• 9 Mudenda S, Chabalenge B, Daka V. et al. Global strategies to combat antimicrobial resistance: a one health perspective. Pharmacol Pharm 2023; 14 (08) 271-328
• 10 Guan Q, Xing S, Wang L. et al. Triazoles in medicinal chemistry: physicochemical properties, bioisosterism, and application. J Med Chem 2024; 67 (10) 7788-7824
• 11 Ahmad I, Khan H, Serdaroğlu G. Physicochemical properties, drug likeness, ADMET, DFT studies, and in vitro antioxidant activity of oxindole derivatives. Comput Biol Chem 2023; 104: 107861
• 12 Irfan A, Batool F, Zahra Naqvi SA. et al. Benzothiazole derivatives as anticancer agents. J Enzyme Inhib Med Chem 2020; 35 (01) 265-279
• 13 Morsy MA, Ali EM, Kandeel M. et al. Screening and molecular docking of novel benzothiazole derivatives as potential antimicrobial agents. Antibiotics (Basel) 2020; 9 (05) 221
• 14 Haroun M, Tratrat C, Kositsi K. et al. A. New benzothiazole-based thiazolidinones as potent antimicrobial agents design, synthesis and biological evaluation. Curr Top Med Chem 2018; 18 (01) 75-87
• 15 Haroun M, Tratrat C, Petrou A. et al. Exploration of the antimicrobial effects of benzothiazolylthiazolidin-4-one and in-silico mechanistic investigation. Molecules 2021; 26 (13) 4061
• 16 Haroun M, Petrou A, Tratrat C. et al. Discovery of benzothiazole-based thiazolidinones as potential anti-inflammatory agents: anti-inflammatory activity, soybean lipoxygenase inhibition effect and molecular docking studies. SAR QSAR Environ Res 2022; 33 (06) 485-497
• 17 Ugwu DI, Okoro UC, Ukoha PO, Gupta A, Okafor SN. Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies. J Enzyme Inhib Med Chem 2018; 33 (01) 405-415
• 18 Ferreira LLG, Andricopulo AD. ADMET modeling approaches in drug discovery. Drug Discov Today 2019; 24 (05) 1157-1165
• 19 Duarte Y, Márquez-Miranda V, Miossec MJ, González-Nilo F. Integration of target discovery, drug discovery and drug delivery: A review on computational strategies. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2019; 11 (04) e1554
• 20 Rask-Andersen M, Almén MS, Schiöth HB. Trends in the exploitation of novel drug targets. Nat Rev Drug Discov 2011; 10 (08) 579-590
• 21 Djuidje EN, Barbari R, Baldisserotto A. et al. Benzothiazole derivatives as multifunctional antioxidant agents for skin damage: structure–activity relationship of a scaffold bearing a five-membered ring system. Antioxidants 2022; 11 (02) 407
• 22 Kale A, Kakde R, Pawar S, Thombare R. Recent development in substituted benzothiazole as an anticonvulsant agent. Mini Rev Med Chem 2021; 21 (08) 1017-1024
• 23 Ramaiah MJ, Karthikeyan D, Mathavan S. et al. Synthesis, in vitro and structural aspects of benzothiazole analogs as anti-oxidants and potential neuroprotective agents. Environ Toxicol Pharmacol 2020; 79: 103415
• 24 Ahmadi A, Khalili M, Sohrabi L, Delzendeh N, Nahri-Niknafs B, Ansari F. Synthesis and evaluation of the hypoglycemic and hypolipidemic activity of sulfonamide-benzothiazole derivatives of benzylidene-2,4- thiazolidnedione. Mini Rev Med Chem 2017; 17 (08) 721-726
• 25 Asiri YI, Alsayari A, Muhsinah AB, Mabkhot YN, Hassan MZ. Benzothiazoles as potential antiviral agents. J Pharm Pharmacol 2020; 72 (11) 1459-1480
• 26 Venugopala KN, Chandrashekharappa S, Pillay M. et al. Synthesis and structural elucidation of novel benzothiazole derivatives as anti-tubercular agents: in-silico screening for possible target identification. Med Chem 2019; 15 (03) 311-326
• 27 Venugopala KN, Khedr MA, Pillay M. et al. Benzothiazole analogs as potential anti-TB agents: computational input and molecular dynamics. J Biomol Struct Dyn 2019; 37 (07) 1830-1842
• 28 Venugopala KN, Krishnappa M, Nayak SK. et al. Synthesis and antimosquito properties of 2,6-substituted benzo[d]thiazole and 2,4-substituted benzo[d]thiazole analogues against Anopheles arabiensis. Eur J Med Chem 2013; 65: 295-303
• 29 Jung W, Goo S, Hwang T. et al. Absorption distribution metabolism excretion and toxicity property prediction utilizing a pre-trained natural language processing model and its applications in early-stage drug development. Pharmaceuticals (Basel) 2024; 17 (03) 382
• 30 Guan L, Yang H, Cai Y. et al. ADMET-score - a comprehensive scoring function for evaluation of chemical drug-likeness. MedChemComm 2018; 10 (01) 148-157
• 31 Odame F, Schoeman R, Krause J. et al. Synthesis, characterization, crystal structures, and anticancer activity of some new 2,3-dihydro-1,5-benzoxazepines. Med Chem Res 2021; 30: 987-1004
• 32 Chiou CT, Kile DE. Effects of polar and nonpolar groups on the solubility of organic compounds in soil organic matter. Environ Sci Technol 1994; 28 (06) 1139-1144
• 33 Tiwari R, Möllmann U, Cho S, Franzblau SG, Miller PA, Miller MJ. Design and syntheses of anti-tuberculosis agents inspired by BTZ043 using a scaffold simplification strategy. ACS Med Chem Lett 2014; 5 (05) 587-591
• 34 Franzblau SG, DeGroote MA, Cho SH. et al. Comprehensive analysis of methods used for the evaluation of compounds against Mycobacterium tuberculosis . Tuberculosis (Edinb) 2012; 92 (06) 453-488
• 35 Drapal M, Fraser PD. Metabolite profiling: a tool for the biochemical characterisation of Mycobacterium sp . Microorganisms 2019; 7 (05) 148
• 36 Tsui CKM, Wong D, Narula G, Gardy JL, Hsiao WWH, Av-Gay Y. Genome sequences of the Mycobacterium tuberculosis H37Rv-ptkA deletion mutant and its parental strain. Genome Announc 2017; 5 (44) e01156-17
• 37 Arora K, Ochoa-Montaño B, Tsang PS. et al. Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis . Antimicrob Agents Chemother 2014; 58 (11) 6962-6965
• 38 van der Westhuyzen R, Winks S, Wilson CR. et al. Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: a novel antimycobacterial class targeting mycobacterial respiration. J Med Chem 2015; 58 (23) 9371-9381
• 39 Ollinger J, Bailey MA, Moraski GC. et al. A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis . PLoS One 2013; 8 (04) e60531
• 40 Nabi M, Tabassum N, Ganai BA. Phytochemical screening and antibacterial activity of Skimmia anquetilia N.P. Taylor and Airy Shaw: a first study from Kashmir Himalaya. Front Plant Sci 2022; 13: 937946
• 41 Amenu JD, Neglo D, Abaye DA. Comparative study of the antioxidant and antimicrobial activities of compounds isolated from solvent extracts of the roots of Securinega virosa . J Biosci Med 2019; 7 (08) 27-41
• 42 Mahmoud A, Afifi MM, El Shenawy F, Salem W, Elesawy BH. Syzygium aromaticum extracts as a potential antibacterial inhibitors against clinical isolates of Acinetobacter baumannii: an in-silico-supported in-vitro study. Antibiotics (Basel) 2021; 10 (09) 1062
• 43 Ayensu I, Quartey AK. Antimicrobial activities of the stem bark of Trichilia Tessmannii (Harms) and Trichilia Monadelpha (Thonn) J.J. De Wilde, both of the family Meliaceae. World J Pharm Pharm Sci 2015; 4 (09) 1351-1362
• 44 Anderson DG, Salm S, Beins M. Nester's microbiology: a human perspective. 10th eds.. New York: McGraw-Hill; 2021
• 45 Feher M, Schmidt JM. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci 2003; 43 (01) 218-227
• 46 Elnima EI, Zubair MU, Al-Badr AA. Antibacterial and antifungal activities of benzimidazole and benzoxazole derivatives. Antimicrob Agents Chemother 1981; 19 (01) 29-32
• 47 Xiong G, Wu Z, Yi J. et al. ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res 2021; 49 (W1): W5-W14
• 48 Dong J, Wang NN, Yao ZJ. et al. ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. J Cheminform 2018; 10 (01) 29
• 49 Park M, Kim D, Kim I, Im SH, Kim S. Drug approval prediction based on the discrepancy in gene perturbation effects between cells and humans. EBioMedicine 2023; 94: 104705
• 50 Ursu O, Rayan A, Goldblum A. et al. Understanding drug-likeness. Wiley Interdiscip Rev Comput Mol Sci 2011; 1: 760-781
• 51 Bernardi A, Drew Bennett WF, He S. et al. Advances in computational approaches for estimating passive permeability in drug discovery. Membranes 2023; 13 (11) 851
• 52 Sarkar B, Islam SS, Ullah MA. et al. Computational assessment and pharmacological property breakdown of eight patented and candidate drugs against four intended targets in Alzheimer's disease. Adv Biosci Biotechnol 2019; 10 (11) 405-430
• 53 Halip L, Avram S, Curpan R. et al. Exploring DrugCentral: from molecular structures to clinical effects. J Comput Aided Mol Des 2023; 37 (12) 681-694
• 54 Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J Med Chem 2001; 44 (12) 1841-1846
• 55 Harley BK, Neglo D, Tawiah P. et al. Bioactive triterpenoids from Solanum torvum fruits with antifungal, resistance modulatory and anti-biofilm formation activities against fluconazole-resistant candida albicans strains. PLoS One 2021; 16 (12) e0260956
• 56 Rati R, Patel J, Rishi S. Vulvovaginal candidiasis and it antifungal susceptibility pattern: single center experience. Int J Medical Research Review 2015; 3 (01) 72-78
• 57 Silva AC, Santana EF, Saraiva AM. et al. Which approach is more effective in the selection of plants with antimicrobial activity?. Evid Based Complement Alternat Med 2013; 2013: 308980
• 58 Mogana R, Adhikari A, Tzar MN, Ramliza R, Wiart C. Antibacterial activities of the extracts, fractions and isolated compounds from Canarium patentinervium Miq. against bacterial clinical isolates. BMC Complement Med Ther 2020; 20 (01) 55
• 59 Kumar N, Goel N. Phenolic acids: Natural versatile molecules with promising therapeutic applications. Biotechnol Rep (Amst) 2019; 24: e00370
• 60 Singh M, Singh SK, Gangwar M, Nath G, Singh SK. Design, synthesis and mode of action of some benzothiazole derivatives bearing an amide moiety as antibacterial agents. RSC Adv 2014; 4 (36) 19013-19023
• 61 Mohamed EAK. Hepatoprotective effect of aqueous leaves extract of Psidium guajava and Zizyphus spina-christi against paracetamol induced hepatotoxicity in rats. J Appl Sci Res 2012; 8 (05) 2800-2806
• 62 Stefaniak M, Olszewska B. 1,5-Benzoxazepines as a unique and potent scaffold for activity drugs: a review. Arch Pharm (Weinheim) 2021; 354 (12) e2100224
• 63 Shi W, Zhang Y. PhoY2 but not PhoY1 is the PhoU homologue involved in persisters in Mycobacterium tuberculosis . J Antimicrob Chemother 2010; 65 (06) 1237-1242