Abstract
A series of 2-chloro-5-[(4-chlorophenyl)sulfamoyl]-N-(alkyl/aryl)-4-nitrobenzamide derivatives (5a–5v) has been synthesized and confirmed by physicochemical(Rf, melting point) and spectral means (IR, 1HNMR, 13CNMR). The results of in vitro antidiabetic study against α-glucosidase indicated that compound 5o bearing 2-CH3-5-NO2 substituent on phenyl ring was found to be the most active compound against both enzymes. The electron donating (CH3) group and electron withdrawing (NO2) group on a phenyl ring highly favoured the inhibitory activity against these enzymes. The docking simulations study revealed that these synthesized compounds displayed hydrogen bonding, electrostatic and hydrophobic interactions with active site residues. The structure activity relationship studies of these compounds were also corroborated with the help of molecular modeling studies. Molecular dynamic simulations have been done for top most active compound for validating its α-glucosidase and α-amylase inhibitory potential, RMSD analysis of ligand protein complex suggested the stability of top most active compound 5o in binding site of target proteins. In silico ADMET results showed that synthesized compounds were found to have negligible toxicity, good solubility and absorption profile as the synthesized compounds fulfilled Lipinski’s rule of 5 and Veber’s rule.
Highlights
Diabetes mellitus (DM) is a complex metabolic disorder resulting either due to relative or absolute deficiency of pancreatic insulin secretion or insensitivity to insulin action, ensuing in postprandial hyperglycemia and assorted diabetic complications [1, 2]
Thakral et al BMC Chemistry (2020) 14:49 and Voglibose are currently available drugs used as α-glucosidase and α-amylase inhibitors, but due to their deleterious side effects such as abdominal distention, diarrhoea and bloating, flatulence [8–10] there is need to explore and synthesize new drug candidates for the management of type-II diabetes mellitus with no or low risk of side effects
Benzamides are the carbonic acid amide of benzoic acid and have been described for exhibiting various biological activities i.e. antimicrobial [23, 24], antiinflammatory [25], anticancer [26, 27], antidiabetic [28], antidepressant, antitubercular [29], anticonvulsant [30] and analgesic [31] etc. 2,4-Dichlorobenzoic acid derivatives have been reported for their antidiabetic potential exhibiting α-glucosidase and α-amylase inhibitory activity, as described in our previous studies [32, 33]
Summary
Diabetes mellitus (DM) is a complex metabolic disorder resulting either due to relative or absolute deficiency of pancreatic insulin secretion or insensitivity to insulin action, ensuing in postprandial hyperglycemia and assorted diabetic complications [1, 2]. Benzamides are the carbonic acid amide of benzoic acid and have been described for exhibiting various biological activities i.e. antimicrobial [23, 24], antiinflammatory [25], anticancer [26, 27], antidiabetic [28], antidepressant, antitubercular [29], anticonvulsant [30] and analgesic [31] etc. 2,4-Dichlorobenzoic acid derivatives have been reported for their antidiabetic potential exhibiting α-glucosidase and α-amylase inhibitory activity, as described in our previous studies [32, 33]. Thiazole2-yland N-pyridin-2-yl benzamides from benzoic acids showed glucokinase activation and possessed good antidiabetic potential in animal rat model [35, 36]. A series of sulfamoyl benzamide derivatives have been reported by Grewal et al, having glucokinase activation potential for the treatment of type 2 diabetes [37]. In view of the vital importance of benzamides in management of type 2 diabetes, we have synthesized a series of 2-chloro5-[(4-chlorophenyl)sulfamoyl]-N-(alkyl/aryl)-4-nitrobenzamides and evaluated its antidiabetic potential in the current report
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