Synthesis, crystal structure, Hirshfeld surface analyses, quantum chemical properties, and in silico anti-ferrochelatase potential of N1,N3-bis(2,4-dichlorophenyl)malonamide
Structural Chemistry, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Basım Tarihi: 2026
- Doi Numarası: 10.1007/s11224-026-02860-z
- Dergi Adı: Structural Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO), Materials Science & Engineering Collection (ProQuest), Technology Collection (ProQuest)
- Anahtar Kelimeler: Amidation, Experimental vs theoretical calculations, Ferrochelatase inhibitors, Heme biosynthesis, Malonamide derivatives, Malonic acids
- Hacettepe Üniversitesi Adresli: Evet
Özet
A facile synthesis of N1,N3-bis(2,4-dichlorophenyl)malonamide (DCPM) from malonic acid and 2,4-dichloroaniline using EDC/DMAP-mediated coupling is reported. The structure of DCPM was confirmed by FTIR, 1H- /13C-NMR, and single-crystal X-ray diffraction analyses. Crystallographic studies revealed that DCPM crystallizes in the monoclinic crystal system with the P2₁/c space group. The crystal packing is stabilized by classical intermolecular N–H···O hydrogen bonds, supplemented by weak van der Waals interactions, as confirmed by Hirshfeld surface analysis, which showed that H···H (25.8%), Cl···H/H···Cl (23.2%), C···H/H···C (14.8%), and O···H/H···O (10.8%) contacts make the major contributions to the crystal packing, with no significant voids observed. Density functional theory (B3LYP/6-31G*) calculations showed good agreement between the optimized and experimental molecular geometries. Frontier molecular orbital, molecular electrostatic potential, and TD-DFT analyses revealed pronounced charge separation around the amide carbonyl and N–H groups, explaining the observed intermolecular interactions and electronic transitions. The optimized S₀ geometry was confirmed as a true minimum by vibrational frequency analysis. Molecular docking suggested favorable binding of DCPM within the human ferrochelatase (PDB ID: 1HRK) binding pocket through five hydrogen bonds, one C–H···π interaction, and one π–π stacking interaction, while ADMET predictions indicated acceptable drug-likeness with some predicted toxicity liabilities requiring further experimental validation. Overall, the combined crystallographic and computational investigations provide valuable insight into the structure–property relationships of DCPM and support its potential as a promising scaffold for future ferrochelatase-targeted studies.