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 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 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 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.

An Overview of the Structure–Activity Relationship in Novel Antimicrobial Thiazoles Clubbed with Various Heterocycles (2017–2023)

“…The compounds were tested for their antimicrobial activity against bacterial strains and the C. albicans ATCC 10231 fungal strain [ 23 ]. Compounds 57 – 60 showed superior activity against P. aeruginosa ATCC 29853 (MICs = 15.625–31.25 µg/mL) compared to amoxicillin (MIC > 500 µg/mL).…”

“…Compounds 57 – 60 showed superior activity against P. aeruginosa ATCC 29853 (MICs = 15.625–31.25 µg/mL) compared to amoxicillin (MIC > 500 µg/mL). This activity was inferior (MICs = 62.5–125 µg/mL) against E. coli ATCC 25922 and S. aureus ATCC 25923 compared to the reference (MICs = 7.8–62.5 µg/mL) [ 23 ]. The compounds were also tested against sensitive M. tuberculosis , with compound 59 showing equal activity to isoniazid (MIC = 0.12 µg/mL) [ 23 ].…”

“…Concerning antifungal activity, the compounds showed superior activity (MICs = 3.9–62.5 µg/mL) against C. albicans compared to fluconazole (MIC = 250 µg/mL) [ 23 ].…”

“…Substitution with p -bromophenyl in the fourth position of the thiazole ring increased the antifungal and antituberculosis activities of compound 59 . The presence of an ethyl carboxylate substituent in the fifth position of the thiazole ring in compound 60 slightly decreased the overall antimicrobial activity compared to compounds 57 – 59 ( Figure 13 ) [ 23 ].…”

“…This target has been verified in a DHFR inhibitory efficiency assay, with compound 59 showing better inhibition (IC 50 = 4.21 ± 0.13 µM) compared to trimethoprim (IC 50 = 6.23 ± 0.05 µM). No potential target was reported for antibacterial and antifungal activities [ 23 ].…”