Covalent assistance to supramolecular synthesis: modifying the drug functionality of the antituberculosis API isoniazidin situ during co-crystallization with GRAS and API compounds

Abstract

The anti-tuberculosis molecule isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes and also allows for its biological activity to be improved and modified by a simple covalent reaction. The low temperature crystal structures of both isoniazid (1) and the related N′-(propan-2-ylidene)isonicotinohydrazide molecule (2), the latter known to be a more effective agent against Mycobacterium tuberculosis, are reported. In addition, these two molecules were then co-crystallized with the same three Generally Regarded As Safe (GRAS) molecules, succinic acid, 4-hydroxybenzoic acid and 2-hydroxybenzoic acid, to produce the following pharmaceutical co-crystals: (isonicotinic acid hydrazide)2·(succinic acid) 3, (N′-(propan-2-ylidene)isonicotinohydrazide)2·(succinic acid) 4, (isonicotinic acid hydrazide)·(4-hydroxybenzoic acid) 6, (N′-(propan-2-ylidene)isonicotinohydrazide)·(4-hydroxybenzoic acid) 7, (isonicotinic acid hydrazide)·(2-hydroxybenzoic acid) 8, and (N′-(propan-2-ylidene)isonicotinohydrazide)·(2-hydroxybenzoic acid) 9. In addition, a co-crystal using 2-butanone as a modifier is also reported, (N′-(butan-2-ylidene)isonicotinohydrazide)2·(succinic acid) 5. Drug–drug co-crystals were also made with the anti-HIV compound 2-chloro-4-nitrobenzoic acid: (isonicotinic acid hydrazide)·(2-chloro-4-nitrobenzoic acid) 10, and (N′-(propan-2-ylidene)isonicotinohydrazide)·(2-chloro-4-nitrobenzoic acid) 11. All the co-crystals use the carboxylic acid⋯pyridine hydrogen bond to connect the GRAS or drug molecule to the pyridine ring. In general, the co-crystals with the modified isoniazid feature the C(4) homosynthon, and those with the original isoniazid a variety of homo- and heterosynthons. By comparing the melting points of the co-crystals that use isoniazid and those that use the modified isoniazid, a reduction in melting point is observed.