Synthesis, biological screening and in silico studies of new N-phenyl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine derivatives as potential antifungal and antitubercular agents

• Published in: European journal of medicinal chemistry 2023-10, Vol.258, p.115548-115548, Article 115548
• Main Authors: Nandurkar, Yogesh, Bhoye, Manish R., Maliwal, Deepika, Pissurlenkar, Raghuvir R.S., Chavan, Abhijit, Katade, Sushma, Mhaske, Pravin C.
• Format: Article
• Language: English
• Subjects: Antimicrobial activity; Antitubercular activity; Molecular docking; Molecular dynamics simulations; Pyrazole; Thiazole
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115548

A new series of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) have been synthesized by a cyclo-condensation reaction of 2-bromo-1-(1,3-diphenyl-1H-pyrazol-4-yl)ethanone (6a-f) with N-aryl thiourea, (7a-d). The structure of newly synthesized N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives was analyzed by 1H NMR, 13C NMR and Mass spectral analysis. The compounds 8a-x were screened for in vitro antimicrobial activity against Escherichia coli, Proteus mirabilis, Bacillus subtilis, Staphylococcus aureus, Candida albicans and Aspergillus niger. and antitubercular activity against M. tuberculosis H37Rv strain. Among the twenty-four pyrazolyl-thiazole derivatives, six compounds 8a, 8b, 8j, 8n, 8o and 8s showed good activity against S. aureus. Against A. niger, all synthesized derivatives showed good antifungal activity. Fifteen pyrazolyl-thiazole derivatives 8a, 8f, 8g, 8h, 8j, 8k, 8n, 8o, 8p, 8q, 8r, 8s, 8t, 8w and 8x showed good antitubercular activity with MIC 1.80–7.34 μM (0.8–3.12 μg/mL), these derivatives have showed more activity than the drugs isoniazid and ethambutol. The active compounds were further screened for cytotoxicity activity against the mouse embryonic fibroblast cells (3t3l1) cell lines at 12.5 and 25 μg/mL concentrations and found less or non-cytotoxicity. To know the plausible mode of action, the synthesized pyrazolyl-thiazole derivatives were studied for pharmacokinetics, toxicity profiles and binding interactions along with an in-depth analysis of structural dynamics and integrity using prolonged molecular dynamics (MD) simulation. The compounds have shown significant docking scores in the range of −7.98 to −5.52 and −9.44 to −7.2 kcal/mol with the M. tuberculosis enoyl reductase (M. tb. InhA) and C. albicans sterol 14-α demethylase (C. ab. CYP51), respectively. Thus, the significant antifungal and antitubercular activity of N-aryl-4-(1,3-diaryl-1H-pyrazol-4-yl)thiazol-2-amine, (8a-x) derivatives incited that, these scaffolds could assist in the development of lead compounds to treat fungal and antitubercular infections. [Display omitted] •Synthesis, antimicrobial and antitubercular activity of pyrazolyl-thiazole derivatives.•Fifteen derivatives showed good antitubercular activity with MIC 1.80–7.34 μM.•All compounds showed good antifungal activity against A. niger with MIC 15.62–31.25 μg/mL.•All active derivatives were found non-toxic at 12.5 μg/mL against 3t3l1 cell line.•The in-silico analysis was