Synthesis, Structure‐Activity Relationship and in Silico Studies of Novel Pyrazolothiazole and Thiazolopyridine Derivatives As Prospective Antimicrobial and Anticancer Agents

In our attempt to develop potential new drug candidates with promising dual antimicrobial and anticancer activities, a series of pyrazolothiazole and thiazolopyridine analogues has been synthesized. All compounds were evaluated for their antimicrobial potential towards pathogenic strains and cytotoxicity properties against hepatic cancer cell line HepG-2 and breast cancer cell line MCF-7. 9 c showed excellent antimicrobial activity against the tested strains, with MIC values about 27.5 mu M (S. epidermidis), 6.8 (B. subtilis) and 3.4 mu M (S. pneumoniae and K. pneumoniae) fold higher than the reference drug, whilst 9 a, 9 b and 5 a exhibited also potent activity against selected strains. Moreover, compounds 9 c (IC50=10.89 mu M and 15.60 mu M) and 9 a (IC50=22.24 mu M and 28.47 mu M) showed promising anticancer activity for HepG2 and MCF-7 cell lines, respectively, when compared to the known anticancer drugs, 5-Fluorouracil (IC50=26.75 mu M and IC50=32.75 mu M). The data from structure-activity relationships analysis revealed the potency of pyrazolothiazole than thiazolopyridine derivatives in generating potential activity. Further, molecular docking studies performed on the more active antimicrobial and cytotoxic compound, 9 c to get insights for binding modes to the target enzymes (PDB ID: 1JIJ) for antimicrobial, and (PDB ID: 1DI8) and (PDB ID: 3TWJ) for anticancer revealed that they interacted with the same key amino acids with TyrRS for S. aureus, CDK2 and ROCK1, respectively.