New thiazolyl-isoxazole derivatives as potential anti-infective agents: design, synthesis, in vitro and in silico antimicrobial efficacy

Abstract

Antimicrobial resistance threatens the efficacious prevention and treatment of infectious diseases caused by microorganisms. To combat microbial infections, the need for new drug candidates is essential. In this context, the design, synthesis, antimicrobial screening, and in silico study of a new series of 5-aryl-3-(2-arylthiazol-4-yl)isoxazole (9a-t) have been reported. The structure of new compounds was confirmed by spectrometric methods. Compounds 9a-t were evaluated for in vitro antitubercular and antimicrobial activity. Against M. tuberculosis H37Rv, fourteen compounds showed good to excellent antitubercular activity with MIC 2.01–9.80 µM. Compounds 9a, 9b, and 9r showed four-fold more activity than the reference drug isoniazid. Nine compounds, 9a, 9b, 9d, 9e, 9i, 9q, 9r, 9s, and 9t, showed good antibacterial activity against E. coli with MIC 7.8–15.62 µg/mL. Against A. niger, four compounds showed good activity with MIC 31.25 µg/mL. Against C. albicans, all twenty compounds reported excellent to good activity with MIC 7.8–31.25 µg/mL. Compounds 9c–e, 9g–j, and 9q–t showed comparable activity concerning the reference drug fluconazole. The compounds 9a-t were screened for cytotoxicity against 3t3l1 cell lines and found to be less or non-cytotoxic. The in silico study exposed that these compounds displayed high affinity towards the M. tuberculosis targets PanK, DprE1, DHFR, PknA, KasA, and Pks13, and C. albicans targets NMT, CYP51, and CS. The compound 9r was evaluated for structural dynamics and molecular dynamics simulations. The potent antitubercular and antimicrobial activity of 5-aryl-3-(2-arylthiazol-4-yl)isoxazole (9a–t) derivatives has recommended that these compounds could assist in treating microbial infections.

Communicated by Ramaswamy H. Sarma

Keywords:

• Thiazole
• isoxazole
• antitubercular activity
• antimicrobial activity
• cytotoxicity activity
• in silico study

Acknowledgments

The authors would like to acknowledge S. P. Mandali Pune for providing infrastructure facilities. We gratefully acknowledge the Ministry of Education, Government of India, for providing the infrastructure facilities under the Rashtriya Uchchatar Shiksha Abhiyan (RUSA 2.0). The authors thank CIF-SPPU, Pune, for spectral analysis and S. P. Mandali’s Bhide Foundation Pune for lending support to their biological activities.

Author contributions

MRB and ADS conducted experiments and analyzed the data. VS ALNS, APC, and PCM analyzed the data, DM and RRSP conducted in silico study, and MRB, APC, RRSP, and PCM wrote the manuscript.

Disclosure statement

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 manuscript.