Conjugates of Degraded and Oxidized Hydroxyethyl Starch and Sulfonylureas: Synthesis, Characterization, and in Vivo Antidiabetic Activity

Abstract

Orally administered drugs usually face the problem of low water solubility, low permeability, and less retention in bloodstream leading to unsatisfactory pharmacokinetic profile of drugs. Polymer conjugation has attracted increasing interest in the pharmaceutical industry for delivering such low molecular weight (Mw) drugs as well as some complex compounds. In the present work, degraded and oxidized hydroxyethyl starch (HES), a highly biocompatible semisynthetic biopolymer, was used as a drug carrier to overcome the solubility and permeability problems. The HES was coupled with synthesized N-arylsulfonylbenzimidazolones, a class of sulfonylurea derivatives, by creating an amide linkage between the two species. The coupled products were characterized using GPC, FT-IR, (1)H NMR, and (13)C NMR spectroscopy. The experiments established the viability of covalent coupling between the biopolymer and N-arylsulfonylbenzimidazolones. The coupled products were screened for their in vivo antidiabetic potential on male albino rats. The coupling of sulfonylurea derivatives with HES resulted in a marked increase of the hypoglycemic activity of all the compounds. 2,3-Dihydro-3-(4-nitrobenzensulfonyl)-2-oxo-1H-benzimidazole coupled to HES10100 was found most potent with a 67% reduction in blood glucose level of the rats as compared to 41% reduction produced by tolbutamide and 38% by metformin.

Access to Cyclic N-Trifluoromethyl Ureas through Photocatalytic Activation of Carbamoyl Azides

“…Moreover, N-arylation under Ullman conditions (Cu, 100 °C, 16 h) to 25 was feasible as well as N-alkylation to ultimately prepare the N-CF 3 analogue of oxatomide, an antihistaminic drug 26. Sulfonylation to tosyl urea, prevalent in antidiabetic drugs, 25 was also possible to furnish 27, among which the structure was also confirmed by crystallographic analysis (for details, see the Supporting Information). The N-CF 3 benzimidazolone core was also amenable to traditional crosscoupling with the bromide moiety undergoing borylation (28), alkylation (29), and amination (30).…”

Design, Synthesis and in Vivo Evaluation of Novel Glycosylated Sulfonylureas as Antihyperglycemic Agents

“…Arylsulfonylurea derivatives were previously synthesized fromhazardous, irritant and moisture sensitive reagents such as arylsulfonyl isocyanates [33,34,35,36]. Later on, safer and more environmentally favorable methodologies have been developed to circumvent the use of these stoichiometric bases [37,38,39,40]. For example, tolbutamide ( N -arylsulfonyl- N ′-alkylureas) was synthesized by reacting benzenesulfonamides with N -alkylthiocarbonates obtained by selenium (or DMSO) assisted carbonylation of amines with carbon monoxide and sulfur [41,42].…”