Synthesis and Anticancer Evaluation of Benzylated Indole Based Alkyl‐Substituted Pyrido[2,3‐d]Pyrimidines Targeting Thymidylate Synthase

AbstractColorectal cancer (CRC) is the second most common cause of cancer‐related deaths and the third most common cancer worldwide. Because of its importance in DNA biosynthesis, thymidylate synthase (TS) has gathered attention as a promising target for cancer therapy. Herein, we have designed and synthesized 12 novel 5‐(N‐Benzyl indol‐3‐yl) pyrido[2, 3‐d] pyrimidine based derivatives and assessed their anticancer activity against HCT 116, MCF‐7, Hep G2, and PC‐3 cell lines. For compounds 5 a and 5 f TS inhibitory activity was also performed along with in silico studies. Further, all the synthesized compounds exhibited anticancer activity, but particularly, compounds 5 a and 5 f were showed excellent anticancer activity having IC50 values of 1.09±0.61, 5.54±0.81, 6.44±0.91, and 5.12±0.65 μM and 1.03±0.96, 3.09±0.52, 4.12±0.59, and 7.06±0.60 μM respectively with control Raltitrexed (IC50 1.02±0.51, 1.88±0.61, 1.30±0.89, and 2.09±0.67 μM respectively) and hTS inhibitory activity with IC50 of 18.91±1.09 and 16.19±0.96 nM with control Raltitrexed (IC50 12.25±1.21 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 5 a and 5 f to the catalytic site of TS. Additionally, ADME characteristics were also in the acceptable range for these compounds. Based on the anticancer activity, SAR was also performed for lead optimization.