Design, synthesis, antimalarial activity, and in-silico studies of new benzimidazole/pyridine hybrids as dihydrofolate reductase inhibitors.

Molecular hybridization of substituted 2-phenylbenzimidazole and pyridine moieties afforded a new series of antimalarial targeting compounds 5a-l. They were assessed against both chloroquine resistant -W2 (CR-W2) and chloroquine sensitive-D6 (CS-D6) strains of P. falciparum. Artemisinin and chloroquine were used as standards drugs. Results revealed that compounds 5e, 5j, 5k and 5l were the most effective against CS-D6 P. falciparum strain with IC values ranged between 0.019 and 0.056 µM and selectivity index values of 7551.95-13642.10. In addition to 5j and 5k derivatives, another four tested compounds 5c, 5d, 5f and 5g exerted effective antimalarial activity against CR-W2 strain of P. falciparum, their IC values were between 0.046 and 0.253 µM with high selectivity index values ranged from 2610.23 to 1024.50. Upon assessing DHFR inhibitory activity of the energetic derivatives, compounds 5j, 5k, and 5e exhibited IC values of 0.72, 3.95, and 5.31 µM, respectively, in comparison to the reference medication trimethoprim, which has an IC of 13.36 µM. Moreover, molecular dynamic simulations and docking experiments were applied to the most active derivative, 5j, into the catalytic binding site of wild-PfDHFR-TS, were done and showed interesting binding profiles and affinities. Furthermore, in silico physicochemical and pharmacokinetic parameters were predicted.