Synthesis and In-Silico Prediction of Pyrimidine Analogues for Anticancer and Antihistaminic Potential

Abstract

Pyrimidines are privileged scaffolds across oncology and allergy therapeutics. We designed and synthesized two focused libraries of pyrimidine analogues—(A) 4,6-disubstituted dihydropyrimidinones (DHPMs) via a Biginelli strategy (n = 16) targeting thymidylate synthase (TS) and cyclin-dependent kinase 2 (CDK2), and (B) 2-anilino-4-(alkoxy)-pyrimidines bearing a distal tertiary amine (n = 12) targeting the human histamine H1 receptor (H1R). In-silico docking suggested sub-micromolar binding modes for lead A-07 (predicted ΔGbind −10.1 kcal/mol to TS; −9.2 kcal/mol to CDK2) and B-05 (−10.3 kcal/mol to H1R). MM-GBSA rescoring corroborated rank ordering. Drug-likeness and ADMET predictions indicated oral bioavailability for 22/28 molecules (Lipinski compliant; low hERG liability) with acceptable metabolic stability. A 2D-QSAR (training n = 20; test n = 8) explained docking-derived pKd with r² = 0.81, Q²_LOO = 0.73, RMSEtest = 0.41. This work presents tractable syntheses and computational evidence prioritizing pyrimidine analogues for dual therapeutic exploration in oncology and antihistamine discovery.