Crystal Engineering of Naturally Occurring Seselin To Obtain Cocrystal with Enhanced Anti-Leishmanial Activity, Hirshfeld Surface Analysis, and Computational Insight

Seselin (8,8-dimethyl-2H,8H-benzo[1,2-b:3,4-b']dipyran-2-one) is a naturally occurring pyrano coumarin, isolated from Seseli diffusum (Roxb. ex Sm., Sant. & Wagh.). We have synthesized the cocrystal of seselin with thiourea by using liquid-assisted grinding and solution methods (via refluxing). The purity and homogeneity of the seselin/thiourea (1:1) cocrystal were confirmed by analysis based on the single-crystal X-ray diffraction technique. A deep insight into the geometry of the cocrystal demonstrated that 1:1 cocrystal stoichiometry is sustained by N-H center dot center dot center dot O hydrogen bonding between amine (-NH2) groups of thiourea and the carbonyl group of seselin. The synthesized cocrystal exhibited good anti-leishmanial activity in vitro (IC50 = 13.2 +/- 1.2 mu g/mL) in comparison to seselin (IC50 = 29.4 +/- 1.0 mu g/mL) and thiourea (IC50 = 86.06 +/- 0.6 mu g/mL), against the tested standards, pentamidine (IC50 = 5.09 +/- 0.09 mu g/mL) and amphotericin B (IC50 = 0.29 +/- 0.05 mu g/mL). Geometrical values of the computationally optimized structure were calculated by density functional theory at B3LYP/6-31(d,p) to obtain the highest occupied molecular orbitals and lowest unoccupied molecular orbitals of the cocrystal, and were found to be consistent with X-ray diffraction data. Hence, this study further highlights the significance of cocrystallization toward improving the efficacy of medicinal and industrial materials. Furthermore, the consistency of computational results with crystallographic values ensured the computational modeling of cocrystals is equally important to predict the stable geometries and next-generation applications of cocrystals.