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
Publisher
University of Nairobi
Rights
Attribution-NonCommercial-NoDerivs 3.0 United StatesUsage Rights
http://creativecommons.org/licenses/by-nc-nd/3.0/us/Collections
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