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 derived semicarbazones could be further exploited for its multi-targeted role in development of anti-neurodegenerative agents.A library of 2-amino-5-nitrothiazole derived semicarbazones (4–21) was designed, synthesised and evaluated for in vitro MAO and ChE inhibitory activity. Compounds 4, 21 and 17 (shown) have emerged as lead MAO-B (IC50:0.212 µM, competitive and reversible), AChE (IC50:0.264 µM, mixed and reversible) and BuChE (IC50:0.024 µM, mixed and reversible) inhibitor respectively. SAR studies disclosed several structural aspects significant for potency and selectivity and indicated the role of size of aryl binding site in potency and selectivity towards MAO-B. Antioxidant activity and neurotoxicity screening results further suggested their multifunctional potential for the therapy of neurodegenerative diseases.
Highlights
The present growth in the state-of-art medical technologies has resulted in the augmentation in the average life expectancy, among the elderly population, the consequences of which include social and complex issues like neurodegenerative diseases (NDDs)
Monoamine oxidase B (MAO-B) activity is reported to be increased in association with gliosis, which can result in higher levels of hydrogen peroxide and oxidative stress for vulnerable neurons affected by NDDs3
The 18 new 2-amino-5-nitrothiazole derived SCZs 4–21 presented in this work were prepared through a well-established synthetic route illustrated in Scheme 1 in accordance with the standard reaction conditions[49]
Summary
The present growth in the state-of-art medical technologies has resulted in the augmentation in the average life expectancy, among the elderly population, the consequences of which include social and complex issues like neurodegenerative diseases (NDDs). Because of the complex and multifactorial nature of NDDs and diverse cerebral mechanisms implicated in their treatment, it is unlikely that a monotherapy will provide a comprehensive and satisfactory therapeutic solution. Such therapy is more likely to be achieved by the use of multitarget-directed ligands (MTDLs) that incorporate several pharmacological traits into a single molecular entity and work in a synergistic manner. The MTDL strategy targeting monoamine oxidases (MAO-A and MAO-B) and cholinesterases (ChE) namely acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)) represents one of the promising approaches due to their validated neuroprotective, neurorestorative and cognition enhancing capability in addition to their effect on monoaminergic neurotransmission[6,8]. Attempts to combine anti-MAO and anti-ChE activities in one molecular entity have previously been reported[9,10,11,12,13]
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