Design, synthesis, and pharmacological evaluation of 2-amino-5-nitrothiazole derived semicarbazones as dual inhibitors of monoamine oxidase and cholinesterase: effect of the size of aryl binding site

Journal of Enzyme Inhibition and Medicinal Chemistry
Rati K P TripathiSenthil R Ayyannan

Abstract

A series of 2-amino-5-nitrothiazole derived semicarbazones were designed, synthesised and investigated for MAO and ChE inhibition properties. Most of the compounds showed preferential inhibition towards MAO-B. Compound 4, (1-(1-(4-Bromophenyl)ethylidene)-4-(5-nitrothiazol-2-yl)semicarbazide) emerged as lead candidate (IC50 = 0.212 µM, SI = 331.04) against MAO-B; whereas compounds 21 1-(5-Bromo-2-oxoindolin-3-ylidene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0.264 µM) and 17 1-((4-Chlorophenyl) (phenyl)methylene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC50 = 0.024 µM) emerged as lead AChE and BuChE inhibitors respectively; with activity of compound 21 almost equivalent to tacrine. Kinetic studies indicated that compound 4 exhibited competitive and reversible MAO-B inhibition while compounds 21 and 17 showed mixed-type of AChE and BuChE inhibition respectively. Docking studies revealed that these compounds were well-accommodated within MAO-B and ChE active sites through stable hydrogen bonding and/or hydrophobic interactions. This study revealed the requirement of small heteroaryl ring at amino terminal of semicarbazone template for preferential inhibition and selectivity towards MAO-B. Our results suggest that 5-nitrothiazole...Continue Reading

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Citations

Aug 1, 2018·The ISME Journal· WasimuddinSimone Sommer
Mar 3, 2020·Mini Reviews in Medicinal Chemistry·Su-Min WuJuan Sun
Jul 3, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Derya OsmaniyeGülhan Turan
Jun 27, 2020·Journal of Biomolecular Structure & Dynamics·Githa Elizabeth MathewHoon Kim
Sep 24, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Begüm Nurpelin SağlıkZafer Asım Kaplancıklı
Jan 4, 2019·Medicinal Research Reviews·Rati Kailash Prasad Tripathi, Senthil Raja Ayyannan

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