Design, synthesis, and biological evaluation of some methyl 2-(1H-pyrazol-4-ylthio)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives as potential DHFR inhibitors

Abstract

Drug-resistant bacteria pose an increasingly serious threat to mankind all over the world. However, the currently available clinical treatments do not meet the urgent demand. Therefore, it is desirable to find new targets and inhibitors to overcome the problems of antibiotic resistance. Dihydrofolate reductase (DHFR) is an important enzyme required to maintain bacterial growth, and hence inhibitors of DHFR have been proven as effective agents for treating bacterial infections. In the present work, we have designed some methyl 2-(1H-pyrazol-4-ylthio)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives as potential DHFR inhibitors through rational drug design approach. The designed derivatives were screened through Lipinski rule, Veber’s rule, ADMET analysis, drug-likeness properties, and molecular docking. All the compounds demonstrated more potent activity than Ampicillin against both gram-positive and gram-negative bacteria. Most of the compounds were more or equipotent than Chloramphenicol and Ciprofloxacin. Compound A7 was sensitive at 25 µg/mL against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus whereas compound A20 was sensitive to all gram +ve and –ve bacteria at same concentration. Compound A16 was sensitive at 50 µg/mL against all the bacteria. In antifungal activity, compound A7 exhibited MFCs of 100 µg/mL against Candida albicans, Aspergillus niger, and Aspergillus clavatus which is same as Nystatin.