Synthesis of sulfonylureas containing one and two carbon linkers as potential antidiabetic drugs

Abstract

Target compounds (10a–r) coming from different amines (morpholine, piperidine, propyl, pyrrolidine) were synthesized using a three reaction protocol. In two of the reaction steps nucleophilic substitution was used; the intermediate reaction where amines were being added and the final steps where different isocynates were being used. The target compounds were characterized using 1H NMR, 13C NMR, IR and HRMS. Some of the target compounds were screened for their antidiabetic activity against α- glucosidase, α - amylase and the AGE formation. The screening results showed that the compounds tested against α-glucosidase did not present any significant activity at concentrations 100 μM and 200μM. At the same concentration, the results for AGE formation showed that only three compounds, 10k, 10h and 10j, showed some activity. Some compounds had the strongest α- amylase inhibition (IC50 10-12 μM), 10h, 10o and 10m with an IC50 of 11.71±3.64, 12.06±0.00 and 10.42±0.00 respectively. Compounds 10p and 10r showed moderate inhibition (IC50, 31 -44 μM), compounds 10p and 10r had an IC50 of 43.62±6.05 and 35.07±0.00 respectively. Computational study was also performed and the results showed acceptable ADME and drug likeness properties and were presumed safe for further studies. Compounds 10l, 10e and 10r have emerged as potent inhibitors against SGLT2 with a docking score of −7.999 kcal/mol, −7.657kcal/mol and −7.626 kcal/mol respectively. Both Root Mean Square Deviation (RMSD) and Root-Mean-Square Fluctuation (RSMF) have shown good structural stability throughout the simulation between 1.5-2.0Å. Additionally, DFT calculations provided insights into the electronic distribution and reactivity of the lead compounds, suggesting that these compounds have the potential to be further investigated as a next treatment for type 2 diabetes mellitus (T2DM). iii DEDIC