Pharmaceutical analysis combined with in-silico therapeutic and toxicological profiling on zileuton and its impurities to assist in modern drug discovery

Ganorkar, Saurabh B.; Heyden, Yvan Vander; Shirkhedkar, Atul A.; Lokwani, Deepak K.; Dhumal, Dinesh; Bobade, Preeti S.

doi:10.1016/j.jpba.2019.112982

Cited by 13 publications

(5 citation statements)

References 26 publications

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“…As for 5‐LOX enzyme, zileuton belonged to the group of chelating inhibitors of the 5‐LOX, chelating the active iron (Fe) site of the enzyme. [ 35 ] The hydroxyl group of the hydroxyl urea part of zileuton showed metal interaction with Fe 2+ region in the active site of 5‐LOX enzyme, with an energy score of −6.3 kcal/mol (Figure 10). Moreover, it showed hydrogen bond interaction with Asn554, the important amino acid in the 5‐LOX active site.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of pyrazolone analogues as potential anti‐inflammatory agents targeting cyclooxygenases and 5‐lipoxygenase

Shabaan

Kamal

Faggal

et al. 2020

Archiv der Pharmazie

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New pyrazolone derivatives structurally related to celecoxib and FPL 62064 were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases (COXs) and 5‐lipoxygenase (5‐LOX) and their selectivity indices were calculated. The results showed that compounds 3f, 3h, 3l, and 3p have an excellent COX‐2 selectivity index. Moreover, they showed potent 5‐LOX inhibitory activity relative to celecoxib and zileuton, as positive controls. These promising candidates were further investigated for anti‐inflammatory activity using the carrageenan‐induced rat paw edema method and ulcerogenic liability. The results showed no ulceration, which implies their gastric safety profile. Moreover, these compounds were evaluated for prostaglandin (PGE2) production in rat serum. Molecular docking in the COX‐2 and 5‐LOX active sites was performed to rationalize their anti‐inflammatory activities. Strong binding interactions and effective docking scores were identified. The results indicated that these derivatives are good leads for dual‐acting COX‐2/5‐LOX inhibitors to be used as potent and safe anti‐inflammatory agents.

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Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of pyrazolone analogues as potential anti‐inflammatory agents targeting cyclooxygenases and 5‐lipoxygenase

Shabaan

Kamal

Faggal

et al. 2020

Archiv der Pharmazie

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“…Zileuton belongs to the group of chelating inhibitors of the 5‐LOX, chelating the active iron (Fe) site of the enzyme. [ 43 ] The proposed binding mode of reference ligand, zileuton (IC 50 = 0.8 µM), showed an affinity value of −80.03 kcal/mol. In zileuton, the carbonyl group of urea moiety is involved in a hydrogen bonding interaction with Asn425, the amino group is stabilized by a hydrophilic interaction with His600, and the hydroxyl group is involved in a hydrogen bonding interaction with Gln363.…”

Section: Resultsmentioning

confidence: 99%

“…The predicted binding site of 5-LOX enzyme has been reported, [42] which Zileuton belongs to the group of chelating inhibitors of the 5-LOX, chelating the active iron (Fe) site of the enzyme. [43] The proposed binding mode of reference ligand, zileuton (IC 50 = 0.8 µM),…”

Section: Molecular Docking Studies Of 3f 3h and 3j In The 5-lox Ementioning

confidence: 99%

Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX‐2/5‐LOX inhibitors

Shaaban

Kamal

Faggal

et al. 2020

Archiv der Pharmazie

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A new series of pyrazoloquinazoline derivatives equipped with different chalcones was designed, synthesized, and identified through 1 H nuclear magnetic resonance (NMR), 13 C NMR, and infrared spectroscopic techniques. Our design strategy of the quinazolinone-privileged scaffold as a new scaffold was based on merging pharmacophores previously reported to exhibit cyclooxygenase-2 (COX-2)/5lipoxygenase (5-LOX) inhibitory activity. All the newly synthesized derivatives were biologically evaluated for COX and 5-LOX inhibitory activity and COX-2 selectivity, using celecoxib and zileuton as reference drugs, as they exhibited promising antiinflammatory activity. Compound 3j was found to be the most promising derivative, with IC 50 values of 667 and 47 nM against COX-1 and COX-2, respectively, which are superior to that of celecoxib (IC 50 value against COX-2 = 95 nM), showing an SI of 14.2 that was much better than celecoxib. Compounds 3f and 3h exhibited COX-1 inhibition, with IC 50 values of 1,485 and 684 nM, respectively. The synthesized compounds showed a significant inhibitory activity against 5-LOX, with IC 50 values ranging from 0.6 to 4.3 µM, where compounds 3f and 3h were found to be the most potent derivatives, with IC 50 values of 0.6 and 1.0 µM, respectively, in comparison with that of zileuton (IC 50 = 0.8 µM). These promising derivatives, 3f, 3h, and 3j, were further investigated in vivo for anti-inflammatory, gastric ulcerogenic effects, and prostaglandin production (PGE2) in rat serum. The molecular docking studies concerning the binding sites of COX-2 and 5-LOX revealed similar orientation, compared with reported inhibitors, which encouraged us to design new leads targeting COX-2 and 5-LOX as dual inhibitors, as a new avenue in anti-inflammatory therapy.

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“…First, 53 bicyclic compounds from our library were cherry-picked and evaluated in silico, since the benzo[ b ]thiophene moiety is considered the pharmacophore of zileuton . This approximation is due to the absence of zileuton/5-LOX experimentally resolved structure in the protein data bank (), so only the binding mode, derived from recent molecular docking studies, could be taken into account. , From computer-aided analysis, nine derivatives were filtered and tested in vitro for their 5-LOX inhibitory properties leading to the identification of the indoline compound 43 as the hit compound. Therefore, we decided to design a second library of compound 43 analogues.…”

Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization

et al. 2022

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The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC 50 s of 0.41 ± 0.01 and 0.43 ± 0.10 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosaninduced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.

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Pharmaceutical analysis combined with in-silico therapeutic and toxicological profiling on zileuton and its impurities to assist in modern drug discovery

Cited by 13 publications

References 26 publications

Synthesis and biological evaluation of pyrazolone analogues as potential anti‐inflammatory agents targeting cyclooxygenases and 5‐lipoxygenase

Synthesis and biological evaluation of pyrazolone analogues as potential anti‐inflammatory agents targeting cyclooxygenases and 5‐lipoxygenase

Design, synthesis, and biological evaluation of new pyrazoloquinazoline derivatives as dual COX‐2/5‐LOX inhibitors

Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization

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