Chemistry, anti-diabetic activity and structural analysis of substituted dihydropyrimidine analogues

Interplay of Halogen and Hydrogen Bonding through Co–Crystallization in Pharmacologically Active Dihydropyrimidines: Insights from Crystal Structure and Energy Framework

“…Our previous work on structural analysis of DHPM molecules described that HB interactions such as N−H⋅⋅⋅O, O−H⋅⋅⋅O, etc., are the major and preferred interactions in their molecular assembly [26,27,29] . Further, it is also pointed out that HB interactions preferred the formation of a dimeric motif, though it is has also been observed in a few cases that the substituents present on the phenyl ring of DHPM also participated in additional short contacts in their molecular packing.…”

“…The compound 2b (methyl 6‐methyl‐4‐(4‐nitrophenyl)‐2‐oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate) shows many biological applications, namely, calcium channel blockers, anti‐cancer agents etc [21,30] . The hydroxy based DHPM 2d (Ethyl 4‐(4‐hydroxyphenyl)‐6‐methyl‐2‐oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate) also shows hypoglycemic activity [29] . In the current study, co‐crystallization experiments (Scheme 2), in substituted DHPM molecules (2a–d), with 1,4‐diiodo tetrafluorobenzene (1,4 DITFB) and 3‐nitrobenzoic acid (3 NBA) have been performed by exploring the formation of possible halogen bonding (XB) and hydrogen bonding (HB) hetero‐synthons.…”

“…The DHPM is formed via a simple one‐pot multicomponent reaction between an aldehyde, β‐ketoester, and urea/thiourea in ethanol with an acidic medium, which was first discovered by Pietro Biginelli in 1893 [18] . The compounds are well documented in the literature for their biological activity [19–29] . However, it is essential to improve the pharmacological activity (different physico‐chemical properties) of biologically active compounds as a function of time and hence co‐crystallization is a viable approach.…”

“…[18] The compounds are well documented in the literature for their biological activity. [19][20][21][22][23][24][25][26][27][28][29] However, it is essential to improve the pharmacological activity (different physico-chemical properties) of biologically active compounds as a function of time and hence cocrystallization is a viable approach. The co-crystals have been obtained by mechanochemical or solution-based approaches to enhance the pharmacological and physicochemical properties of drug molecules.…”

“…[28] Our previous work on structural analysis of DHPM molecules described that HB interactions such as NÀ H•••O, OÀ H•••O, etc., are the major and preferred interactions in their molecular assembly. [26,27,29] Further, it is also pointed out that HB interactions preferred the formation of a dimeric motif, though it is has also been observed in a few cases that the substituents present on the phenyl ring of DHPM also participated in additional short contacts in their molecular packing. With the current understanding from the different crystal structures of DHPM based molecules in this study, we propose that this homo synthon [Scheme 1(c)] can be replaced with heterosynthon formation, utilizing either halogen bonding (XB) [Scheme 1(a)-(b)] or hydrogen bonding [Scheme 1(d)].…”