Hydrazonoyl bromide precursors as DHFR inhibitors for the synthesis of bis-thiazolyl pyrazole derivatives; antimicrobial activities, antibiofilm, and drug combination studies against MRSA

• Published in: Bioorganic chemistry Vol. 116; p. 105339
• Main Authors: Ibrahim, Seham A., Fayed, Eman A., Rizk, Hala F., Desouky, Said E., Ragab, Ahmed
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.11.2021; Elsevier
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiofilm; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antimicrobial; Biochemistry & Molecular Biology; Biofilms - drug effects; Bis-thiazolyl pyrazole; Chemistry; Chemistry, Organic; DHFR inhibitors; Dose-Response Relationship, Drug; Drug combination; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fungi - drug effects; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Humans; Hydrazonoyl bromide; In silico studies; Life Sciences & Biomedicine; MIC and MBC activities; Microbial Sensitivity Tests; Molecular Structure; Physical Sciences; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Science & Technology; Structure-Activity Relationship; Synthesis; Tetrahydrofolate Dehydrogenase - metabolism; Antimicrobial; In silico studies; Drug combination; Synthesis; Antibiofilm; MIC and MBC activities; DHFR inhibitors; Bis-thiazolyl pyrazole; Hydrazonoyl bromide; DESIGN; ANTIBACTERIAL; DISCOVERY; HETEROCYCLES; DIHYDROFOLATE-REDUCTASE; BIOLOGICAL EVALUATION; STAPHYLOCOCCUS-AUREUS
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105339

[Display omitted] •A series of new bis-thiazolyl pyrazole derivatives 3-6 were synthetized.•Antimicrobial screening activity and MIC and SAR study were evaluated.•MBC, and antibiofilm were evaluated for most active thiazolyl derivatives 3, 4a, 4c, and 5b.•Hemolytic assay, and drug combination study, and DHFR inhibition assay was determined.•Molecular docking was performed inside DHFR (PDB: 1DLS). Microbial resistance is a big concern worldwide, making the development of new antimicrobial drugs difficult. The thiazole and pyrazole rings are important heterocyclic compounds utilized to produce a variety of antimicrobial medications. As a result, a series of new bis-thiazolyl-pyrazole derivatives 3, 4a-c, 5a, b, and 6a-c was synthesized by reacting bis hydrazonoyl bromide with several active methylene reagents in a one-pot reaction. The assigned structure was characterized entirely based on elemental and spectral analyses. The antimicrobial activity represented by MIC was performed using a resazurin-based turbidimetric (TB) assay. The results exhibited good antimicrobial activity against gram-positive strains, especially S. aureus (ATCC6538) while showing poor to moderate activity against gram-negative and fungal strains. Furthermore, the most active derivatives 3, 4a, 4c, and 5b were evaluated for MIC, MBC, antibiofilm, hemolytic assay, and drug combination testing against two S. aureus (ATCC6538) and MRSA (ACL18) strains. Additionally, bis-thiazolyl pyrazole 3, 4c, and 5b exhibited more potent inhibitory activity for DHFR with IC50 values (6.34 ± 0.26, 7.49 ± 0.28, and 3.81 ± 0.16 µM), respectively, compared with Trimethoprim (8.34 ± 0.11 µM). The bis-1-(substituted-thiazol-2-yl)-1H-pyrazole-4-carbonitrile derivative 5b was the most active member with MIC values ranging from (0.12–0.25 µM) compared to Vancomycin (1–2 µM), and MBC values ranging from (0.5–1 µM) for S. aureus (ATCC6538) and MRSA (ACL18). Surprisingly, compound 5b displayed bactericidal behavior, synergistic effect with three commercial antibiotics, and inhibited DHFR with 2.1 folds higher than Trimethoprim. Finally, good findings were obtained from in silico investigations incorporating toxicity prediction and molecular docking simulation.