New Thiophenyl-pyrazolyl-thiazole Hybrids as DHFR Inhibitors: Design, Synthesis, Antimicrobial Evaluation, Molecular Modeling, and Biodistribution Studies.

The antibiotic resistance problems constitute a considerable threat to human health worldwide; thus, the discovery of new antimicrobial candidates to conquer this issue is an imperative requirement. From this view, new thiophenyl-pyrazolyl-thiazole hybrids 3-10 were synthesized and screened for their antibacterial efficiency versus Gram - and Gram + bacterial strains compared to the reference drug amoxicillin. It was noticed that the new hybrids displayed significant antibacterial efficacy versus Gram - bacteria, especially against Pseudomonas aeruginosa . Also, all the screened candidates demonstrated a noticeable antifungal effect against Candida albicans (MICs = 3.9-125 μg/mL) relative to fluconazole (MIC = 250 μg/mL). Moreover, the new hybrids were investigated for their antituberculosis potency against Mycobacterium tuberculosis (RCMB 010126). Derivatives 4c , 6b , 8b , 9b, and 10b demonstrated prominent antituberculosis efficiency (MICs = 0.12-1.95 μg/mL) compared with the reference drug isoniazid (MIC = 0.12 μg/mL). The latter derivatives were further assessed for their inhibitory potency versus M. tuberculosis DHFR enzyme. The compounds 4c , 6b and 10b presented a remarkable suppression effect with IC 50 values of 4.21, 5.70, and 10.59 μM, respectively, compared to that of trimethoprim (IC 50 = 6.23 μM). Furthermore, biodistribution profile using radiolabeling way revealed a perceived uptake of 131 I-compound 6b into infection induced models. The docking study for the new hybrids 4c , 6b , 8b , 9b and 10b was performed to illustrate the various binding modes with Mtb DHFR enzyme. In silico ADMET studies for the most potent inhibitors 4c , 6b and 10b were also accomplished to predict their pharmacokinetic and physicochemical features.