Mechanochemistry: Fundamentals, applications and future

Co-crystals of antibiotics with natural antimicrobials: product diversity resulting from different synthetic approaches Cecilia Fiore 1 , Oleksii Shemchuk 2 , Alessandra Baraghini 3 , Simone d’Agostino 1 , Vittorio Sambri 3,4 , Manuela Morotti 3 , Silvia Zannoli 3 , Fabrizia Grepioni 1 and Dario Braga 1 1 Dipartimento di Chimica “Giacomo Ciamician”, Università di Bologna, Italy, 2 Institute of Condensed Matter and Nanosciences, UCLouvain, Belgium, 3 U.O. Microbiologia - Laboratorio Unico Centro Servizi AUSL Romagna, Italy, 4 Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università di Bologna, Italy The phenomenon of antimicrobial resistance is one of the major medical challenges in most healthcare systems [1] in which common pathogenic strains are developing antibiotic-resistant genes. The quest for new antimicrobial agents obtained through conventional organic synthesis can nowadays be supplemented by supramolecular interactions designed with a crystal engineering approach[2]. Recently Desiraju et al. reported a multicomponent solid consisting of an antibacterial (norfloxacin) and an antimicrobial (sulfathiazole) showing enhancement of in vitro biological activity and improved physicochemical behavior [3]. Following this path, we apply co-crystallization strategies as a viable, eco-friendly, and inexpensive way to obtain new materials with modified properties [4,5]. In our latest work [6] we have prepared and structurally characterized co-crystals of three similar antibiotics of the cephalosporin (CFS) class, namely cephalexin, cefradine, and cefaclor, with thymol as the co-former. The reaction between cephalosporins and thymol was performed using three different methods: solution, slurry, and mechanochemical liquid-assisted grinding, with resulting product diversity and stability. In recent work [7], we have reported that co-crystallization of the antibiotic ciprofloxacin with thymol and carvacrol shows an increment in the antibacterial activity as compared to the starting materials and their physical mixtures. The project herein presents analogous experiments, involving the antibiotics of the CFS class, which unexpectedly show a significant increase in the minimal inhibitory concentration. References 1. Brown and Wright, Nature , 2016 , 529, 336. 2. Wouters, Quéré, Pharmaceutical salts and co-crystals , Royal Society of Chemistry, 2011 . 3. Gopi, Ganguly , Desiraju, Mol. Pharm. , 2016 , 13, 3590. 4. Shemchuk, Braga, Grepioni, Turner, RSC Adv. , 2020 , 10, 2146. 5. Fiore, Shemchuk, Grepioni, Turner, Braga, CrystEngComm , 2021 , 23, 4494.

6. Fiore, Baraghini, Shemchuk, Sambri, Morotti, Grepioni, Braga, Cryst. Growth Des . 2022 , 22, 1467. 7. Shemchuk, d’Agostino, Fiore, Sambri, Zannoli, Grepioni, Braga, Cryst. GrowthDes. , 2020 , 20, 6796.

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