Synthesis and structural elucidation of a trifluoromethylated cyclopentene hydrazone: A combined X-ray and computational studies

Abstract

A novel compound, benzoylhydrazo-2-trifluoroacetylcyclopent-1-ene (1), was successfully synthesized via the condensation of benzohydrazide and 2-trifluoroacetylcyclopentan-1-one. Structural confirmation was achieved through elemental analysis, NMR spectroscopy and single-crystal X-ray diffraction. Both solution and solid-state analyses confirmed the exclusive formation of the open-chain structure 1, with no evidence of its fused bicyclic derivative (3-hydroxy-3-(trifluoromethyl)-3a,4,5,6-tetrahydrocyclopenta[c]pyrazol-2(3H)-yl)(phenyl)methanone (1'), and the hydrazone form N'-(2-(2,2,2-trifluoroacetyl)cyclopentylidene)benzohydrazide (1''). Crystallographic analysis revealed that compound 1 exists as two geometrically distinct molecules in the solid state: a nearly planar form (1a) and a conformation (1b) where the benzoyl group is almost orthogonal to the core. Each molecule is stabilized by an intramolecular N-H•••O hydrogen bond. These bonds further facilitate intermolecular assembly, whereby molecules of 1b form centrosymmetric dimers that subsequently connect to molecules of 1a, creating an extended 1D supramolecular chain through a network of hydrogen bonds. The DFT calculations corroborated the experimental findings, indicating that the optimized structure aligns with conformation 1b and is energetically more stable than the potential forms 1' and 1''. While compound 1 was classified in the low-acutetoxicity Class IV, the model flagged potential concerns for neurotoxicity, nephrotoxicity and carcinogenicity, among others. These predicted activities represent key areas requiring rigorous experimental follow-up. On a positive note, the absence of predicted hepatotoxicity and cardiotoxicity is encouraging, as these are common causes of drug candidate attrition. Most significantly, molecular docking studies predicted a strong binding affinity for hemoglobin S (-8.8 kcal/mol), surpassing that of the approved drug Voxelotor (-7.1 kcal/mol). All calculated ligand efficiency scores for 1 fell within the range characteristic of Hit, highlighting its significant potential for development as a therapeutic inhibitor for sickle cell disease.