In silico ADMET study, docking, synthesis and antimalarial evaluation of thiazole-1,3,5-triazine derivatives as Pf-DHFR inhibitor.

Background: Plasmodium falciparum dihydrofolate reductase (Pf-DHFR) is an essential enzyme in the folate pathway and is an important target for antimalarial drug discovery. In this study a modern approach has been undertaken to identify new hits of thiazole-1,3,5-triazine derivatives as antimalarials targeting Pf-DHFR.

Methods: The library of 378 thiazole-1,3,5-triazines were designed and subjected to ADME analysis. The compounds having optimal ADME score, was then evaluated by docking against wild and mutant Pf-DHFR complex. The resultant compound after screening from above these two methods were synthesized, and assayed for in vitro antimalarial against chloroquine-sensitive (3D-7) and chloroquine resistant (Dd-2) strains of P. falciparum.

Results: Twenty compounds were identified from the dataset based on considerable AlogP98 vs. PSA_2D confidence ellipse, ADME filter and TOPKAT toxicity analysis. Majority of compounds showed interaction with Asp54, Arg59, Arg122 and Ile 164 in docking analysis. Entire set of tested derivatives exhibited considerable activity at the tested dose against sensitive strain with IC values varying from 10.03 to 54.58 μg/ml. Furthermore, against chloroquine resistant strain, eight compounds showed IC from 11.29 to 40.92 μg/ml. Compound A5 and H16 were found to be the most potent against both the strains of P. Falciparum.

Conclusion: Results of the study suggested the possible utility of thiazole-1,3,5-triazines as new lead for identifying new class of Pf-DHFR inhibitor.