Fighting Antibiotic Resistance: New Pyrimidine-Clubbed Benzimidazole Derivatives as Potential DHFR Inhibitors

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 2; p. 501
• Main Authors: Haque, M Akiful, Marathakam, Akash, Rana, Ritesh, Almehmadi, Samar J, Tambe, Vishal B, Charde, Manoj S, Islam, Fahadul, Siddiqui, Falak A, Culletta, Giulia, Almerico, Anna Maria, Tutone, Marco, Khan, Sharuk L
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.01.2023; MDPI
• Subjects: ADMETlab 2.0; Anti-Bacterial Agents - pharmacology; antibacterial; Antibacterial agents; Antibiotic resistance; Antibiotics; antifungal; Bacteria; Benzimidazoles; Benzimidazoles - pharmacology; Bioavailability; Chloramphenicol; Chloromycetin; Ciprofloxacin; Coliforms; Design; DHFR; Dihydrofolate reductase; Drug resistance; Drug Resistance, Microbial; E coli; Enzymes; Folic Acid Antagonists - pharmacology; Fungal infections; Fungicides; Gram-negative bacteria; Gram-positive bacteria; Hydrogen bonds; Imidazole; Inhibitors; Ligands; Metabolism; Microbial Sensitivity Tests; Molecular docking; Molecular Docking Simulation; Molecular Structure; Nosocomial infections; Permeability; Proteins; Pseudomonas aeruginosa; pyrimidines; Pyrimidines - pharmacology; Reductases; Staphylococcus infections; Strains (organisms); Structure-Activity Relationship; Tropical diseases; DHFR; antifungal; molecular docking; ADMETlab 2.0; antibacterial; benzimidazoles; pyrimidines
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28020501

The present work describes the design and development of seventeen pyrimidine-clubbed benzimidazole derivatives as potential dihydrofolate reductase (DHFR) inhibitors. These compounds were filtered by using ADMET, drug-likeness characteristics calculations, and molecular docking experiments. Compounds , , , , , , and were chosen for the synthesis based on the results of the in silico screening. Each of the synthesized compounds was tested for its in vitro antibacterial and antifungal activities using a variety of strains. All the compounds showed antibacterial properties against Gram-positive bacteria ( and ) as well as Gram-negative bacteria ( and ). Most of the compounds either had a higher potency than chloramphenicol or an equivalent potency to ciprofloxacin. Compounds and were effective against all the bacterial and fungal strains. Finally, the 1,2,3,4-tetrahydropyrimidine-2-thiol derivatives with a 6-chloro-2-(chloromethyl)-1 -benzo[ ]imidazole moiety are potent enough to be considered a promising lead for the discovery of an effective antibacterial agent.