Larvicidal study of tetrahydropyrimidine scaffolds against Anopheles arabiensis and structural insight by single crystal X‐ray studies

Abstract

A series of methyl or ethyl 4-(substitutedphenyl/pyridyl)-6-methyl-2-oxo/thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (HPM) analogues 4a-g were synthesized and evaluated for larvicidal activity against Anopheles arabiensis. These newly synthesized compounds were characterized by spectral studies such as FT-IR, NMR ( H and C), LC-MS, and elemental analysis. The conformational features and supramolecular assembly of molecules 4a, 4b, and 4e were further analyzed from single crystal X-ray study. The larvicidal activity of these tetrahydropyrimidine pharmacophore series was analyzed based on their relative substituents. Among the synthesized HPM analogous from the series, compounds 4d and 4e both having electron withdrawing chlorine group on phenyl ring at the fourth position of the tetrahydropyrimidine pharmacophore exhibited the most promising larvicidal activity.

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

“…The crystal structures of 2a, 2c and 2d have already been reported in the literature [26,27] whereas in the current study, we only report the crystal structure of 2b (Table S1). This allows for the comparison of the structure of 2b with their obtained co‐crystals (C2aXB, C2bXB, C2cXB, C2dHB) and the solvatomorph (S2c).…”

“…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 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.…”

“…In this context, we have chosen four different DHPM based molecules, with various functional groups as substituents on the phenyl ring, such as hydroxy, nitro, and chlorine along with the presence of urea/thiourea moiety. The DHPM based molecules 2a (Methyl 4‐(4‐hydroxyphenyl)‐6‐methyl‐2‐oxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate and 2c (Methyl 4‐(2‐chlorophenyl)‐6‐methyl‐2‐thioxo‐1,2,3,4‐tetrahydropyrimidine‐5‐carboxylate exhibit good larvicidal activity but low antidiabetic activity [26,27] . 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] .…”

Larvicidal Activities of 2-Aryl-2,3-Dihydroquinazolin -4-ones against Malaria Vector Anopheles arabiensis, In Silico ADMET Prediction and Molecular Target Investigation

“…In continuation of our efforts in developing larvicidal agents [35][36][37][38][39][40] and pharmacologically active heterocyclic compounds via green and microwave methods [41][42][43], we report herein the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives, a biological evaluation of their larvicidal activity against Anopheles arabiensis, and an in silico evaluation of their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties as well as molecular target investigation. In recent years, green and sustainable chemistry drew much attention for the generation of new chemical methods with less environmental impact.…”