NOVEL BENZOTHIAZOLE-ISATIN HYBRIDS: MICROWAVE SYNTHESIS AND COMPUTATIONAL INSIGHTS AGAINST MULTIDRUG-RESISTANT TUBERCULOSIS

THIRUMALA ROOPESH G; GEETHAVANI M

doi:10.22159/ajpcr.2025v18i9.55471

Authors

THIRUMALA ROOPESH G Department of Pharmaceutical Chemistry, Balaji College of Pharmacy, Anantapuramu-515001, Andhra Pradesh, India.
GEETHAVANI M Research Scholar, Department of Pharmaceutical Sciences, JNTUA, Anantapuramu, Andhra Pradesh, India. https://orcid.org/0000-0002-1466-9317

DOI:

https://doi.org/10.22159/ajpcr.2025v18i9.55471

Keywords:

Benzothiazole derivatives, Antitubercular activity, Molecular docking, Mass spectrometry, Binding energy, MABA, AutoDock, PyRx, Discovery studio,, PyMoL

Abstract

Objective: Multidrug-resistant tuberculosis (MDR-TB) is the outcome of Mycobacterium tuberculosis developing resistance to at least isoniazid or rifampicin, the two most effective first-line anti-TB drugs. A major worldwide health concern, this resistance makes treatment regimens more challenging and necessitates the development of new therapeutic agents and medication delivery methods. A class of heterocyclic chemicals called benzothiazole derivatives is well-known for its many biological actions, including antibacterial, antitubercular, anticancer, & anti-inflammatory properties. Recent studies have shown that these compounds hold promise in the use of both laboratory and computer-based techniques to create novel medications, particularly against drug-resistant illnesses.

Methods: In the current research, several new benzothiazole-based molecules were synthesized and evaluated for their antitubercular potential using both experimental testing and molecular modelling. Out of the synthesized compounds, Histidine, Serine, Valine, Phenylalanine and Tyrosine derivatives showed notable activity against Mycobacterium tuberculosis at a concentration of 3.12 µg/ml, which is similar to that of pyrazinamide, a common medication. While compound IG showed decreased activity at 12.5 µg/ml, compounds such as tryptophan derivatives, proline, glutamic acid, and cysteine showed considerable activity at 6.25 µg/ml. Mass spectrometry and FTIR were used to verify the purity and chemical structure of every produced molecule. Standard protocols recorded their physical characteristics, such as solubility, melting point, or R_fvalues. To conduct molecular docking investigations, AutoDock 4.2.6 was used, and PyRx software against the Protein Data Bank ID: 2JA2 protein target.

Results: The compound (ITRYPT)Tryptophan Derivative showed the strongest binding energy of –8.8 kcal/mol, better than the standard drugs and the co-crystal ligand Acetate ion (ACT) (–5.3 kcal/mol). Other active compounds such as (IH) Histidine, (IP) Proline, (IS) serine, and (IAA) Aspartic acid derivatives also showed strong binding energies between -8.8 and -8.3 kcal/mol. In-depth interaction analyses showed that these substances created pi-cation interactions, π–π stacking, & hydrogen bonding. With key amino acids like Trp67, Arg271, Asp272 in the protein's active site. Toxicity was predicted using the PROTOX-3 server, and the results indicated that the compounds were within acceptable safety limits.

Conclusion: Overall, Tryptophan derivative and other active derivatives have shown encouraging results and may be considered for further biological studies and structure-activity relationship (SAR) analysis to develop effective antitubercular agents.

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References

1. Gaonkar SL, Hakkimane SS, Bharath BR, Shenoy VP, Vignesh UN, Guru BR. Stable isoniazid derivatives: In silico studies on Mycobacterium tuberculosis enoyl-ACP reductase (InhA). Asian J Pharm Clin Res. 2020;13(10):131-6.

2. Shaikh FM, Patel NB, Sanna G, Busonera B, La Colla P, Rajani DP. Synthesis of some new 2-amino-6-thiocyanato benzothiazolederivatives bearing 2,4-thiazolidinediones and screening of their in vitro antimicrobial, antitubercular and antiviral activities. Med Chem Res. 2015;24(8):3129-42. doi: 10.1007/s00044-015-1358-0

3. Arul K, Sunisha KS. In-silico design, synthesis and in vitro anticancer and antitubercular activity of novel azetidinone-containing isatin derivatives. Int J Pharm Pharm Sci. 2014;6(9):506-13.

4. Varpe BD, Jadhav SB. Schiff base of isatin with 2-thiopheneethylamine and its Mannich bases: Synthesis, docking, and in vitro anti-inflammatory and antitubercular activity. Russ J Bioorg Chem. 2022;48(2):372-9. doi: 10.1134/S1068162022020030.

5. Hakim F, Salfidoer SR. Antibacterial and antitubercular activity of novel benzothiazole-aryl amine derivatives tethered through acetamide functionality. Asian J Chem. 2021;33(8):1757-63. doi: 10.14233/ ajchem.2021.23226

6. Salina EG, Postiglione U, Chiarelli LR, Recchia D, Záhorszká M, Lepioshkin A, et al. A novel class of antitubercular compounds targeting the bacterial respiratory chain. mSphere. 2022;7:e00369-22.

7. Hemeda LR, El Hassab MA, Abdelgawad MA, Khaleel EF, Abdel-Aziz MM, Binjubair FA, et al. Discovery of pyrimidine-tethered benzothiazole derivatives as novel anti-tubercular agents towards multi- and extensively drug resistant Mycobacterium tuberculosis. J Enzyme Inhib Med Chem. 2023;38(1):2250575. doi: 10.1080/14756366.2023.2250575, PMID: 37649381

8. DrugBank. Ethambutol. Available from: https://www.drugbank.ca/ drugs/DB00339

9. DrugBank. Streptomycin. Available from: https://www.drugbank.ca/ drugs/DB01082

10. DrugBank. Pyrazinamide. Available from: https://www.drugbank.ca/ drugs/DB01045

11. DrugBank. Isoniazid. Available from: https://www.drugbank.ca/drugs/ DB00951

12. DrugBank. Rifampicin. Available from: https://www.drugbank.ca/ drugs/DB00330

13. Eldehna WM, El Hassab MA, Abdelshafi NA, Al-Zahraa Sayed F, Fares M, Al-Rashood ST, et al. Development of potent nanosized isatin-isonicotinohydrazide hybrids for management of Mycobacterium tuberculosis. Int J Pharm. 2022;612:121369. doi: 10.1016/j. ijpharm.2021.121369, PMID: 34906651

14. Cheke RS, Patil VM, Firke SD, Ambhore JP, Ansari IA, Patel HM, et al. Therapeutic outcomes of isatin and its derivatives against multiple diseases: Recent developments in drug discovery. Pharmaceuticals (Basel). 2022;15(3):272. doi: 10.3390/ph15030272, PMID: 35337070

15. Capela R, Félix R, Clariano M, Nunes D, Perry MJ, Lopes F. Target identification in anti-tuberculosis drug discovery. Int J Mol Sci. 2023;24(13):10482. doi: 10.3390/ijms241310482, PMID: 37445660

16. Sekine S, Nureki O, Shimada A, Vassylyev DG, Yokoyama S. Crystal Structure of a Translation Initiation Factor. London: Nature; 2001.

17. Kassem AF, Sabt A, Korycka-Machala M, Afifi MM, El Sayed I, Swairjo MA, et al. Identification of quinoline-isatin hybrids as InhA inhibitors against Mycobacterium tuberculosis. Indian J Clin Res. 2024;144:107138.

18. Yadav R, Meena D, Singh K, Tyagi R, Yadav Y, Sagar R. Recent advances in the synthesis of new benzothiazole based anti-tubercular compounds. RSC Adv. 2023;13(32):21890-925. doi: 10.1039/ d3ra03862a, PMID: 37483662

19. Anand SR, Kumar K, Bairwa DD, Meena RP, Bagoria R, Sharma S, et al. In silico Evaluation of Benzothiazole Hybrids against MDR Tuberculosis. United Kingdom: Qeios; 2024. p. 1-13.

20. Zala M, Vora JJ, Khedkar VM. Synthesis, characterization, antitubercular activity, and molecular docking studies of pyrazolylpyrazoline-clubbed triazole and tetrazole hybrids. ACS Omega. 2023;8(23):20262-71. doi: 10.1021/acsomega.2c07267, PMID: 37323386

21. Selvaraju K, Manimekalai A. Synthesis, characterization and antimicrobial evaluation of some new benzothiazole derivatives. Rasayan J Chem. 2017;10:25-31.

22. Venugopala KN, Khedr MA, Pillay M, Nayak SK, Chandrashekharappa S, Aldhubiab BE, et al. Benzothiazole analogs as potential anti-TB agents: Computational input and molecular dynamics. J Biomol Struct Dyn. 2019;37(7):1830-42. doi: 10.1080/07391102.2018.1470035, PMID: 29697293

23. Thakkar SS, Thakor P, Ray A, Doshi H, Thakkar VR. Benzothiazole analogues: Synthesis, characterization, MO calculations with PM6 and DFT, in silico studies and in vitro antimalarial as DHFR inhibitors and antimicrobial activities. Bioorg Med Chem. 2017;25(20):5396-406. doi: 10.1016/j.bmc.2017.07.057, PMID: 28789907

24. Bhoi MN, Borad MA, Pithawala EA, Patel HD. Novel benzothiazole containing 4H-pyrimido[2,1-b]benzothiazoles derivatives: One pot, solvent-free microwave assisted synthesis and their biological evaluation. Arab J Chem. 2019;12(8):3799-813. doi: 10.1016/j. arabjc.2016.01.012

25. Sultana S, PP, Rajkamal B. Microwave-assisted synthesis, molecular docking studies and biological evaluation of benzothiazole-carrying indole derivatives. Asian J Chem. 2021;33(11):2755-61.

26. Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-61. doi: 10.1002/ jcc.21334, PMID: 19499576.

27. Dassault Systèmes BIOVIA. Discovery Studio Visualizer. v21.1.0.20298. San Diego: Dassault Systèmes; 2021.

28. DeLano WL. The PyMOL Molecular Graphics System. San Carlos, CA: DeLano Scientific; 2002.

29. Lourenço MC, de Souza MV, Pinheiro AC, Ferreira ML, Gonçalves RS, Nogueira TM, et al. Synthesis of isatin-thiosemicarbazone derivatives with antitubercular activity. Arkivoc. 2007; (Part-i):181-91.

30. Bharath BR, Hakkimane SS, Gaonkar SL, Shenoy VP, Guru BR. Structure-based virtual screening and ADME prediction of potential inhibitors targeting enoyl ACP reductase of Mycobacterium tuberculosis. Int J Appl Pharm. 2020;12(4):205-10.

31. Rahman H, Rahman MS, Rahman M. Computational evaluation of toxicity and pharmacokinetics of some bioactive phytochemicals using PROTOX-II and SwissADME tools. Int J Appl Pharm. 2021;13(6):90-4.

32. Sood S, Gupta S, Arora S. Molecular docking and ADMET study of benzothiazole derivatives as antimicrobial agents. Int J Pharm Pharm Sci. 2021;13(9):51-6.

33. Patel H, Thakor P, Dave J. In silico docking analysis of selected phytochemicals with DHFR enzyme of Mycobacterium tuberculosis. Int J Curr Pharm Res. 2019;11(6):18-21.

34. Suthar J, Patel J, Patel K, Patel R. In silico prediction of biological activity, toxicity and drug-likeness of curcumin analogs using PASS, PROTOX-II and ADMETlab. Int J Appl Pharm. 2022;14(2):167-72.

35. Azmi MN, Hasmaruddin NS, Mat Ali NA, Osman H, Mohamad S, Parumasivam T, et al. Synthesis, characterization, anti-mycobacterial activity and in silico study of new 2,5-disubstituted-1,3,4-oxadiazole derivatives. Trop Biomed. 2022;39(3):467-75. doi: 10.47665/ tb.39.3.019, PMID: 36214446