A novel cocrystal of 5-fluorouracil with 2,2’-dipyridylamine: Synthesis, structural characterization, thermal analysis and in silico anticancer evaluation as a thymidylate synthase inhibitor

•A cocrystal of 5-fluorouracil (5-FU) with 2,2’-dipyridylamine (dpya) was prepared.•The cocrystal had a 3D-network formed via hydrogen bonds and π-π interactions.•The cocrystal displayed increased thermal stability compared to dpya.•Anticancer potential of the cocrystal was investigated through molecular docking.•The cocrystal showed stronger thymidylate synthase inhibition than 5-FU and FdUMP. A new cocrystal containing 5-fluorouracil (5-FU) and 2,2’-dipyridylamine (dpya) was successfully prepared by a slow evaporation solution method and characterized using solid-state techniques such as FTIR, thermal analysis (DTA/TG) and single crystal X-ray diffraction. X-ray crystallography indicated the formation of a 2:1 5-FU:dpya cocrystal. The 5-FU and dpya molecules in the cocrystal were linked by N−H···O, N−H···N, C−H···O and C−H···F hydrogen bonds, forming a two-dimensional layers, further extended to a three dimensional supramolecular network via π-stacking interactions. Thermal analysis data showed that the cocrystal exhibited a lower thermal stability than 5-FU, but it is more stable than dpya. Molecular docking method was used to investigate in silico anticancer activity of the new co-crystal against a cancer target protein, human thymidylate synthase (TS). The free binding affinity of the cocrystal towards TS was notably higher than those of both reference ligands 5-FU and 5-fluorodeoxyuridine monophosphate (FdUMP), indicating the enzyme inhibition and anticancer potential of the cocrystal. Additionally, the molecular dynamics (MD) simulation and binding free energy studies confirmed the stability of the TS-cocrystal complex in a period of 50 ns. [Display omitted]