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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 50 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 50 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 50 values of 0.72, 3.95, and 5.31 µM, respectively, in comparison to the reference medication trimethoprim, which has an IC 50 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1-18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)