Discovery of benzo[g]indol-3-carboxylates as potent inhibitors of microsomal prostaglandin E2 synthase-1 (original) (raw)
Related papers
European journal of medicinal chemistry, 2018
The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E synthase-1 (mPGES-1), that block, at the same time, the formation of PGE and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogue...
Biomolecules
The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 M, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good...
Discovery of Benzo[f]indole-4,9-dione Derivatives as New Types of Anti-Inflammatory Agents
International journal of molecular sciences, 2015
Certain benzo[f]indole-4,9-dione derivatives were synthesized and evaluated for their inhibitory effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. Results indicated that (Z)-1-benzyl-4-(hydroxyimino)-1H-benzo[f]indol-9(4H)-one (10) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 value of 2.78 and 2.74 μM respectively. The action mechanisms of 10 in human neutrophils were further investigated. Our results showed that compound 10 did not alter fMLF-induced phosphorylation of Src (Src family Y416). Notably, phosphorylation of Akt (S473) and mobilization of [Ca2+]i caused by fMLF was inhibited by compound 10. Further structural optimization of 10 is ongoing.
Drug Discovery of New Anti-Inflammatory Compounds by Targeting Cyclooxygenases
Pharmaceuticals, 2022
The goal of achieving anti-inflammatory efficacy with the fewest possible adverse effects through selective COX-2 inhibition is still being investigated in order to develop drugs with safe profiles. This work shows the efficacy and safety profile of two novel benzimidazole piperidine and phenoxy pyridine derivatives in reaching this goal, which would be considered a major achievement in inflammatory therapy. The compounds were evaluated by virtual screening campaign, in vitro cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition, in vivo carrageenan-induced rat paw edema assay, cytotoxicity against Raw264.7 cells, and histopathological examination of rat paw and stomach. Two new compounds, compound 1 ([(2-{[3-(4-methyl-1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)amino]acetic acid) and compound 2 (ethyl 1-(5-cyano-2-hydroxyphenyl)-4-oxo-5-phenoxy-1,4-dihydropyridine-3-carboxylate) showed high selectivity against COX-2, favourable drug-likeness and ADME descriptors, a lack of cy...
New ring-extended analogs of indomethacin were designed based on the structure of active binding site of both COX-1 and COX-2 isoenzymes and the interaction pattern required for selective inhibition of COX-2 to improve its selectivity against COX-2. The strategy adopted for designing the new inhibitors involved i) ring extension of indomethacin to reduce the possibility of analogs to be accommodated into the narrow hydrophobic tunnel of COX-1, ii) deletion of carboxylic acid to reduce the possibility of inhibitor to form salt bridge with Arg120 and eventually prevent COX-1 inhibition, and iii) introduction of methylsulfonyl group to increase the opportunity of the analogs to interact with the polar side pocket that's is crucial for inhibition process of COX-2. The three series of tetrahydrocarbazoles involving 4, 5, 9, 10 and 12 were synthesized in quantitative yields adopting limited number of reaction steps, and applying laboratory friendly reaction conditions. In vitro and in vivo assays for data profiling the new candidates revealed the significant improvement in the potency and selectivity against COX-2 of 6-methoxytetrahydrocarbazole 4 (IC 50 ¼ 0.97 mmol) to verify the effect of ring extension in comparison to indomethacin (IC 50 ¼ 2.63 mmol), and 6-methylsulfonyltetrahydrocarbazole 10a (IC 50 ¼ 0.28 mmol) to verify the effect of ring extension and introduction of methylsulfonyl group. 9-(4-chlorobenzoyl)-6-(methylsulfonyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one 12a showed the most potential and selective activity against COX-2 (IC 50 ¼ 0.23 mmol) to be with superior potency to Celecoxib (IC 50 ¼ 0.30 mmol). Consistently, 12a was the most active with all the other anti-inflammatory test descriptors and its activity in diminishing the PGE2 with the other analogs confirmed the elaboration of new class of selective COX-2 inhibitors beyond the diarylsulfonamides as a previously common class of selective COX-2 inhibitors. Molecular docking study revealed the high binding score of compound 12a (À30.78 kcal/mol), with less clash contribution (7.2) that is close to indomethacin. Also, 12a showed low conformation entropy score (1.40). Molecular dynamic (MD) simulation identified the equilibrium of both potential and kinetic energies.
2020
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered the most excessively particular drugs for inflammation treatment including pain releasing, anti-pyretic and rheumatoid arthritis. They inhibit synthesis of prostaglandin by blocking the cyclooxygenation of arachidonic acid (AA) to prostaglandin G2 (PGG2)1. This inhibition process is catalyzed by means of the enzyme cyclooxygenase (COX) of which (COX-1) and (COX-2) are two similar but diverse isoforms of the enzyme24.COX-2 is prompted upon inflammatory motivators and is responsible for