Synthesis And Antiglycemic Activity Of In Silico Designed Analogues Of Allylpropyldisulphide

Abstract

Diabetes is a major global health challenge. The disease has a high prevalence mainly due to change in lifestyle associated with improved economic growth. Sulfonylurea monotherapy, sulfonylurea-biguanide combination therapy and insulin administration are some of the common treatments for type 2 Diabetes mellitus. Some of these drugs have side effects and are expensive, especially to patients in developing countries. Consequently, there is need to identify alternative diabetes drugs inspired by nature that are cheaper with reduced side effects. Although nature continues to provide antiglycemic compounds such as allylpropyldisulphide (ADPS) from onions, their activity is often limited for direct pharmaceutical use. This study exploited the positive attributes of computer-aided drug design in the process of drug discovery to optimize N-({[4- methylphenyl)sulfonyl]amino}methyl)propanamide (2), an analog of APDS, as a potential antiglycemic agent. Ligands were modeled to complement and bind to the target allosteric site of the insulin-degrading enzyme (IDE). Genetic Optimization for Ligand Docking (GOLD); a Cambridge crystallography and data center software application was used to bind ligands to the target and data analyzed in XLSTAT. Moreover, toxicological evaluation was carried out in data warrior; an OSIRIS property explorer tool. The computational study identified N-({[(4- methylphenyl)sulfonyl]amino}methyl)propanamide (2) and N-(1-{[(4- methylphenyl)sulfonyl]amino}-2-phenylethyl)propanamide (16) as attractive compounds for further analysis. The two compounds were synthesized and evaluated In vivo for v antiglycemic activity. Although both compounds exhibited antiglycemic activity, compound 2 was the most potent with maximum blood glucose suppression of 59% observed after an hour while compound 16 suppressed blood glucose by a maximum of 45% after 30 minutes of oral dextrose administration. The antiglycemic activity of compound 2 was comparable to metformin (a standard diabetes drug) where it suppressed blood glucose by 59% after one hour and metformin suppressed the same by 62% after two hours. From the antiglycemic screens, it is recommended that compound 2 be further optimized In silico to identify more potent antiglycemic compounds. S O O NH NH O (2) (16) HN O