DESIGN, SYNTHESIS, AND MOLECULAR DOCKING OF BIPYRIDINE-BASED LIGANDS AS DUAL MODULATORS OF TGF?1 AND ITG?6

Shivaji Bhanothu, Shivalal Banoth, Bukhya Chaitanya Kumar and H. Surekha Rani*

ABSTRACT

Cancer remains a leading global health concern, with increasing incidence and mortality rates attributed to the limited availability of selective and effective anticancer therapies. Pyrimidine-based compounds and bipyridine derivatives have shown a wide range of pharmacological activities, including anticancer potential. In this study, we report the synthesis of 5'-Methoxy-[3,3'-bipyridine]-6-carboxamide via a Suzuki coupling reaction between 3-bromo-5-methoxypyridine and (6-carbamoylpyridin-3-yl) boronic acid using Pd (PPh₃) ₂Cl₂ as a catalyst and K2CO3 as the base. The synthesized compound was characterized using NMR, FT-IR, HRMS, and chromatographic techniques. Ligands derived from this structure were evaluated through molecular docking studies against cancer-associated protein targets TGFβ1 (PDB ID: 1KLC) and ITGβ6 (PDB ID: 4UM8). Docking results revealed favorable binding energies, with SM showing stronger affinity towards ITGβ6 (–7.1 kcal/mol) and SM exhibiting better interaction with TGFβ1 (–6.1 kcal/mol). Detailed interaction analysis indicated key hydrogen bonding and hydrophobic interactions that contribute to the stability of the ligand-protein complexes. Drug-likeness and ADMET predictions further supported the potential of these compounds as therapeutic candidates. The findings provide a promising scaffold for the development of dual-target modulators of TGFβ1 and ITGβ6 pathways, pending further biological and pharmacological validation.

Keywords: pyrimidine derivative, synthesis, anti-cancer, molecular docking.