Synthesis and Antiproliferative Activity against Melanoma Cells of New Heterocyclic Hybrids Based on Pyridine and Pyrimidine Scaffolds.

Abstract

Background: Over 85% of biologically active compounds are heterocycles or contain heterocyclic groups, underscoring their vital importance in contemporary drug development. Among them, nitrogen-containing derivatives, such as pyridines and pyrimidines, are considered privileged structures in approved drugs or are extensively studied due to their promising therapeutic effects.

Objective: In the current work, we would like to verify the hypothesis that incorporating heterocyclic pharmacophores into derivatives of pyrimidine-2(1H)-thione (PMT), 2-pyridone (P), pyridine-2(1H)-thione (PT), dihydropyrimidine-2(1H)-thione (DHPMT), dihydropyridin- 2(1H)-one (DHP), and dihydropyridine-2(1H)-thione (DHPT) rings enhances antitumor activity.

Methods: A range of novel pyridine- and pyrimidine-based compounds were synthesized and assessed for their anticancer properties against the melanoma A375 cell line. The two most potent compounds (16b and 29) were then chosen for further evaluation of their effects on non-cancerous human dermal fibroblasts, cancer cell apoptosis, cell cycle phase distribution, and tubulin polymerization. Furthermore, in silico analyses were performed to assess the pharmacokinetics, toxicity, drug-likeness, and molecular target of the selected compounds.

Results: Among the 33 compounds tested, pyridine analogs 16b and 29 demonstrated the strongest antiproliferative activity (with IC50 values of 1.85 ± 0.44 μM and 4.85 ± 1.67 μM, respectively) and selectivity (SI=65.08 and SI> 100, respectively) against cancer cells. Additional studies revealed that compound 16b, which features a thiophene ring at the C-5 position and a 3,4,5-trimethoxyphenyl (TMP) group, showed the most promising cell cycle arrest and tubulin polymerization inhibition (IC50=37.26 ± 10.86 μM), resulting in cancer cell apoptosis. In silico ADMET analysis confirmed the drug-- likeness of the synthesized compounds.

Conclusion: This research reinforced the significance of heterocyclic rings as valuable pharmacophores. Additionally, it highlighted the antiproliferative and antimitotic potential of modified pyridine derivatives.