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

Abstract

Diabetes mellitus remains a major global health challenge and demands novel antidiabeticchemotypes with improved safety and pharmacokinetic profiles. Hydrazone, guanidine andpyrrol/pyrrolone motifs are privileged scaffolds in current antidiabetic drug discovery, particularly asα-glucosidase and DPP-4 inhibitors or PPAR-γ modulators(11,12,13,14).Here we report thesynthesis, 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), andCompound 4, a highly conjugated diphenylpyrrolone–guanidinesystem 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 bycondensation 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. Diagnosticbands for N–H, C=N and C–N in the IR spectra, together with downfield C=N carbons in the ¹³CNMR spectra, unequivocally supported the proposed hydrazone/guanidine and pyrrolone–ylideneframeworks.SwissADME calculations indicated acceptable physicochemical and drug-likenessprofiles with no major structural alerts.GUSAR-based toxicity modeling predicted moderate acuteoral toxicity (rat LD₅₀ ~ 835 mg·kg⁻¹ for Compound 4; OECD Class 4) and low bioaccumulationpotential.Target-prediction and docking studies suggested favorable binding of both compounds tokey antidiabetic targets (α-glucosidase and PPAR-γ).
This work introduces two new guanidine-containing chemotypes supported by comprehensivespectral and in-silico evidence and provides a complete experimental framework for their biological evaluation as potential antidiabetic leads.