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

Abstract

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 <b>3-10</b> 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 <i>Pseudomonas aeruginosa</i>. Also, all the screened candidates demonstrated a noticeable antifungal effect against <i>Candida albicans</i> (MICs = 3.9-125 μg/mL) relative to fluconazole (MIC = 250 μg/mL). Moreover, the new hybrids were investigated for their antituberculosis potency against <i>Mycobacterium tuberculosis</i> (RCMB 010126). Derivatives <b>4c</b>, <b>6b</b>, <b>8b</b>, <b>9b,</b> and <b>10b</b> 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 <i>M. tuberculosis</i> DHFR enzyme. The compounds <b>4c</b>, <b>6b</b> and <b>10b</b> presented a remarkable suppression effect with IC₅₀ values of 4.21, 5.70, and 10.59 μM, respectively, compared to that of trimethoprim (IC₅₀ = 6.23 μM). Furthermore, biodistribution profile using radiolabeling way revealed a perceived uptake of ¹³¹I-compound <b>6b</b> into infection induced models. The docking study for the new hybrids <b>4c</b>, <b>6b</b>, <b>8b</b>, <b>9b</b> and <b>10b</b> was performed to illustrate the various binding modes with <i>Mtb</i> DHFR enzyme. In silico ADMET studies for the most potent inhibitors <b>4c</b>, <b>6b</b> and <b>10b</b> were also accomplished to predict their pharmacokinetic and physicochemical features.