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

Dina H Dawood; Manal M Sayed; Sally T K Tohamy; Eman S Nossier

doi:10.1021/acsomega.3c04736

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

ACS Omega. 2023 Oct 13;8(42):39250-39268. doi: 10.1021/acsomega.3c04736. eCollection 2023 Oct 24.

Authors

Dina H Dawood¹, Manal M Sayed², Sally T K Tohamy³, Eman S Nossier^{4

5}

Affiliations

¹ Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, 33 El Bohouth Street, Dokki, Giza 12622, Egypt.
² Labeled Compounds Department, Hot Labs.center, Egyptian Atomic Energy Authority (EAEA), P.O. Box 13759, Cairo, Egypt.
³ Department of Microbiology and Immunology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
⁴ Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt.
⁵ The National Committee of Drugs, Academy of Scientific Research and Technology, Cairo 11516, Egypt.

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.