Design, Synthesis, and Anticancer Assessment of Benzylated Pyrrole-Based Pyrido[2,3-d]Pyrimidines as Thymidylate...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide.
• Thymidylate synthase (TS) is a critical enzyme in DNA synthesis and a validated target for anticancer drugs.

Purpose of the Study:

• To design, synthesize, and evaluate novel benzylated pyrrole-based pyrido[2,3-d]pyrimidines as potential anticancer agents.
• To assess the inhibitory potential of these compounds against thymidylate synthase (TS).

Main Methods:

• Synthesis of 22 pyrido[2,3-d]pyrimidine derivatives using Claisen Schmidt and Michael addition reactions.
• Anticancer activity evaluation against HCT 116, A549, MCF-7, and MDA-MB-231 cancer cell lines.
• In vitro TS enzyme inhibition assays and molecular docking studies.

Main Results:

• Compounds 1c and 2i demonstrated potent TS inhibition (IC50 values of 11.50 ± 1.08 nM and 17.12 ± 0.91 nM, respectively), comparable to the standard drug raltitrexed.
• Molecular docking indicated strong binding affinities for compounds 1c and 2i with the catalytic residue Cys195 of TS.
• Compounds 1c and 2i exhibited good stability in molecular dynamics simulations and favorable drug-like properties.

Conclusions:

• Benzylated pyrrole-based pyrido[2,3-d]pyrimidines, particularly compounds 1c and 2i, are promising lead candidates for developing novel TS inhibitors.
• These compounds warrant further investigation for their therapeutic potential in colorectal cancer and other malignancies.