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Chemical Papers
https://doi.org/10.1007/s11696-018-0520-9
ORIGINAL PAPER
Synthesis, evaluation and docking studies of some 4‑thiazolone
derivatives as eective lipoxygenase inhibitors
Sushant Kumar Shrivastava
1
· Brijesh K. Patel
1
· Prabhash Nath Tripathi
1
· Pavan Srivastava
1
· Piyoosh Sharma
1
·
Avanish Tripathi
1
· Ankit Seth
1
· Manish Kumar Tripathi
1
Received: 9 August 2017 / Accepted: 26 May 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
Some promising 4-thiazolone derivatives as lipoxygenase inhibitors were designed, synthesized, characterized and evaluated
for anti-inflammatory activity and respective ulcerogenic liabilities. Compounds (1b, 1e, 3b, and 3e) exhibited considerable
in vivo anti-inflammatory activity (57.61, 79.35, 75.00, and 79.35%) against carrageenan-induced rat paw edema model,
whereas compounds (1e, 3b, and 3e) were found active against the arachidonic acid-induced paw edema model (55.38, 55.38,
and 58.46%). The most potent compound (3e) exhibited lesser ulcerogenic liability compared to the standard diclofenac and
zileuton. Further, the promising compounds (1e and 3e) were evaluated for in vitro lipoxygenase (LOX; IC
50
= 12.98 µM
and IC
50
= 12.67 µM) and cyclooxygenase (COX) inhibition assay (COX-1; IC
50
> 50 µM and, COX-2; IC
50
> 50 µM). The
enzyme kinetics of compound 3e was evaluated against LOX enzyme and supported by in silico molecular docking and
molecular dynamics simulations studies. Overall, the results substantiated that 5-benzylidene-2-phenyl-4-thiazolones are
promising pharmacophore for anti-inflammatory activity.
Keywords 4-Thiazolone · One-pot multicomponent reaction · Anti-inflammatory · Lipoxygenase
Introduction
Lipoxygenase (LOX) enzyme produces leukotrienes (LTs)
and lipoxins (LXs) from arachidonic acid (AA) LT–LX
metabolism. These are potent inflammatory mediators,
responsible for allergic inflammation and gastric ulceration
(Martel-Pelletier et al. 2003; Shrivastava et al. 2017). The
LOX enzymes exist in human beings in three functional
isoforms 5-, 12-, and 15-LOXs, whereas isoforms 9- and
13-LOX exist in plants (Reddy et al. 2015). The LOX
enzyme generally produce 5-hydroperoxyeicosatetraenoic
acid metabolites (HPETEs) by the addition of molecu-
lar oxygen into the substrate (Carter et al. 1997; Murphy
and Gijón 2007; Srivastava et al. 2016), and generates
inflammatory leukotrienes that regulate inflammation, pain,
and fever, as well as some diverse physiological reactions
such as blood flow, thrombosis, renal and gastrointestinal
functions (Allaj et al. 2013). The LOX enzyme is known as
non-haem iron-containing dioxygenase having an elongated
active cavity without access to the bulk solvent. The enzyme
is lined with both invariant amino acids (Leu368, Leu373,
Leu414, Leu607 and Ile406) and LOX-specific amino acids
(Ala603, Ala606, His600, and Thr364) (Gilbert et al. 2011).
The reported LOX inhibitors show the interactions with
amino acids through respective hydrogen bonding (His372),
hydrophobic (Phe359, Leu414, Leu607, and Ala603) and
electrostatic interactions. However, exploratory research is
required to develop a potent molecule as a drug to clear the
phase trials (Shrivastava et al. 2017).
Zileuton is the most common LOX inhibitor, frequently
prescribed by physicians to treat asthma (Drazen et al. 1999),
inflammation of the upper airway, and chronic obstructive
pulmonary disease (COPD) (Berger et al. 2007). However,
its long-term use is restricted due to side effects such as
dyspepsia (Wenzel and Kamada 1996), and hepatotoxic-
ity (Rossi et al. 2010). Therefore, to discover and develop
the safe and potent LOX inhibitors devoid of toxicities is
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s1169 6-018-0520-9) contains
supplementary material, which is available to authorized users.
* Sushant Kumar Shrivastava
skshrivastava.phe@itbhu.ac.in
1
Department of Pharmaceutical Engineering and Technology,
Indian Institute of Technology (Banaras Hindu University),
Varanasi 221 005, India
@Phil_Robichaud
@deepthiw
@JoseServera