In silico study, synthesis and antimalarial evaluation of hybrid pyridine substituted pyrazole 1,3,5-triazine derivatives.

Malaria is a significant global public health issue, particularly prevalent in Africa, Asia, and Latin America, necessitating urgent research into novel and efficient therapies. In the current research, we have designed pyridine substituted pyrazole 1,3,5-triazine derivatives as antimalarials. A library including 300 compounds, designated as 7S (1-300), has been generated using a variety of aliphatic and aromatic amines. Ten compounds have been selected via in silico screening such as molecular properties, toxicity study, docking study and conventional synthesis for antimalarial evaluation against P. falciparum strains 3D7 (chloroquine-sensitive) and Dd2 (chloroquine-resistant). The docking results of compounds 7s258 and 7s5 revealed higher binding interaction with amino acids Leu46, Phe58, Phe116, Ala16 (-341.33 kcal/mol), Ser111, Ile112, Val45 Pro113, Leu119 (-335.16 kcal/mol) and Phe58, Ser111, Ile112, Phe116 (-354.47 kcal/mol), Phe58, Met55, Leu46, Leu164, Pro113 (-346.34 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR inhibitors. Further these compounds were synthesized by simple nucleophilic substitution reaction and characterized by different spectroscopic methods. The in vitro antimalarial assay results suggested that these compounds exhibit considerable antimalarial activity with IC₅₀ values of 32.74-46.80 μM and 28.05-54.95 μM against both the chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of P. falciparum, respectively. Among the ten derivatives, compound 7s258 and 7s5 show substantial potential as antimalarial agents. They are highly suitable for further refinement in the field of drug development to effectively decrease the global malarial burden.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-024-04129-w.