Trimesic acid–Theophylline and Isopthalic acid–Caffeine Cocrystals: Synthesis, Characterization, Solubility, Molecular Docking, and Antimicrobial Activity

• Published in: Crystal growth & design Vol. 20; no. 5; pp. 3510 - 3522
• Main Authors: Abosede, Olufunso O, Gordon, Allen T, Dembaremba, Tendai O, Lorentino, Carolline M.A, Frota, Heloísa F, Santos, André L.S, Hosten, Eric C, Ogunlaja, Adeniyi S
• Format: Journal Article
• Language: English
• Published: American Chemical Society 06.05.2020
• ISSN: 1528-7483; 1528-7505
• DOI: 10.1021/acs.cgd.0c00301

The preparation of cocrystals from active pharmaceutical ingredients (APIs) and biologically relevant coformers offers the opportunity of obtaining compounds with more desirable physicochemical and biological properties. This work focuses on theophylline–­trimesic acid, caffeine–­isophthalic acid, and caffeine–­trimesic acid cocrystals. All the cocrystals were produced via slow evaporation and were characterized using Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, and single-crystal X-ray diffraction. Structural characterization revealed that interactions such as CO···H, N···H···O, π–π, and C–H···π between the APIs and coformers significantly contribute to crystal packing. Density functional theory studies further revealed the electronic properties of cocrystals, as well as the functional groups that enhance their solubility. Drug activity through the weak groove-binding mode was realized through docking studies of the cocrystals with the DNA structure (Protein Data Bank identifier 1ZEW). Similarly, major interactions, including hydrogen bonding and π-π bonding, were observed between cocrystals and 4HL2, a New Delhi metallo-β-lactamase-1 produced by resistant clinical strains of K. pneumoniae. Biological studies revealed cocrystals with antimicrobial properties, particularly against clinically relevant gram-negative bacterial pathogens (Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa). So, these compounds represent a novel promising group of anti-infective agents.