Molecular docking, toxicity study and in vitro antimalarial evaluation of pyrazole substituted 1,3,5-triazine...

The development of resistance to antimalarial drugs such as chloroquine, amodiaquine, artemisinin, and antifolates is a major health concern, prompting more research into new antimalarial therapies. In the present study, we intend to develop pyrazole substituted 1,3,5-triazine derivatives 7(a-j) as antimalarial agents. These compounds were synthesized using conventional methods and analyzed using various spectroscopic techniques. The docking results showed that compounds 7j and 7i exhibited an excellent binding interactions with PRO A:113, ILE A:164, SER A:111, PHE A:58, LEU A:46, LEU A:119, VAL A:45, ILE A:112 (-204.97to -118.41 kcal/mol) and TYR A:170, CYS A:15, PRO A:113, ILE A:112, ALA A:16, PHE A:58, MET A:55, SER A:111 (-216.24to -152.06 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR-TS. Compounds 7j and 7i exhibited considerable antimalarial efficacy against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of P. falciparum, with IC₅₀ values ranging from 23.78 to 83.36 μM and 30.89-64.24 μM, respectively. These pyrazole-substituted 1,3,5-triazine derivatives could be utilized to find a novel class of Pf-DHFR-TS inhibitors.