DESIGN, SYNTHESIS, SPECTRAL CHARACTERIZATION AND IN-SILICO ANTIDIABETIC EVALUATION OF A HYDRAZONE–CYANOGUANIDINE AND A DIPHENYLPYRROLONE–GUANIDINE CONJUGATE

Abstract

Diabetes mellitus remains a major global health challenge and demands novel antidiabetic chemotypes with improved safety and pharmacokinetic profiles. Hydrazone, guanidine and pyrrol/pyrrolone motifs are privileged scaffolds in current antidiabetic drug discovery, particularly as α-glucosidase and DPP-4 inhibitors or PPAR-γ modulators(11,12,13,14). Here we report the synthesis, full spectroscopic characterization and in-silico evaluation of two new small molecules: Compound 3, an open-chain hydrazone–cyanoguanidine derivative (C₉H₁₂N₄; SMILES: CC(=NN=C(N)N)c1ccccc1), and Compound 4, a highly conjugated diphenylpyrrolone–guanidine system bearing a 4-nitrophenyl moiety, (E)-2-(4-nitrophenyl)-1-((Z)-3-oxo-4,5-diphenyl-1,3-dihydro-2H-pyrrol-2-ylidene)guanidine (C₂₃H₁₇N₅O₃). Both compounds were synthesized by condensation strategies: Compound 3 from acetone phenylhydrazone and cyanoguanidine; Compound 4 from benzil, cyanoguanidine and p-iodonitrobenzene via cyclocondensation and N-arylation. Structures were confirmed by IR, ¹H and ¹³C NMR and mass spectrometry. Diagnostic bands for N–H, C=N and C–N in the IR spectra, together with downfield C=N carbons in the ¹³C NMR spectra, unequivocally supported the proposed hydrazone/guanidine and pyrrolone–ylidene frameworks. SwissADME calculations indicated acceptable physicochemical and drug-likeness profiles with no major structural alerts. GUSAR-based toxicity modeling predicted moderate acute oral toxicity (rat LD₅₀ ~ 835 mg·kg⁻¹ for Compound 4; OECD Class 4) and low bioaccumulation potential. Target-prediction and docking studies suggested favorable binding of both compounds to key antidiabetic targets (α-glucosidase and PPAR-γ).

This work introduces two new guanidine-containing chemotypes supported by comprehensive spectral and in-silico evidence and provides a complete experimental framework for their biological evaluation as potential antidiabetic leads.