Computer Aided Discovery of Potential Anti-inflammatory (S)-naproxen Analogs as COX-2 Inhibitors

Abstract

A series of substituted 2-(6-methoxynapthalen-2-yl) propanoic acid (naproxen) analogs were synthesized. (S)- naproxen (1) was treated with thionyl chloride to yield acid chloride (2) which was then reacted with different heterocyclic moieties and aryl acids to yield the (S)-naproxen analogs (3a-k). All the compounds were screened for antiinflammatory activity using in vivo rat paw oedema model and most of the active ones were investigated for their ulcerogenic potential. In silico studies (molecular modeling and docking) were carried out to recognize the hypothetical binding motif of the title compounds with the cyclooxygenase isoenzymes (COX-1 and COX-2) employing Maestro (Version 9.1, Schrodinger, LLC.) software. 2-(1-(2(2-methoxynaphthalen-6-yl)propanoyl)-1H-indol-2-yl) acetic acid (3k) was found to be the most active compound amongst the series with inhibition of paw edema volume by 62.1%, in silico sitemap score of -0.40kcal/mol and ulcerogenic index as least as 1.19.

Ibuprofen amino acid derivatives: synthesis, docking and biological studies

“…complex, the docking procedure with the lowest root-mean square deviation (RMSD) was used [35], MOE observed the (Ligand-COX-2) complexes with an RMSD root-mean-square deviation of atomic positions range of (1.119587A°-1.991136) for compounds 5-20. The results of (table 1) show that all compounds had accurate binding energies (RMSD< 1 °A), with the exception of acetyl derivatives (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), which had significant RMSD (RMSD > 1°A) for binding energies (table 1). The binding-interaction has improved by adding hydrazide moiety to the orginal compound.…”

“…Thus, we can able to safe retention of these compounds without any effect [37]. All compounds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) were displayed positivity acceptance for blood brain barrier. Permeability of compounds through blood brain barrier (BBB) indicated that these compounds may be effective in treating inflammation.…”

“…The titled compound was synthesized by heating compound (10) with ethanolic hydrazine hydrate solution (40 ml) for 1/2hr. The solvent was removed under vacuum Product 11 was separated as colorless crystals (ethanol), yield 65 %.…”

“…Furthermore, NSAIDs glycol amide nitrate were reported to have less stomach harm when taken orally [9]. m-aminobenzoic acid analogues of NSAIDs have also been reported to be the most efficacious antiinflammatory drugs with less ulcerogenic properties [10]. Furthermore, compared to the parent NSAIDs, the amide prodrug of NSAIDs derivatives demonstrated strong anti-inflammatory action [11].…”

Molecular modeling, synthesis, characterization and pharmacological evaluation of benzo[d]oxazole derivatives as non-steroidal anti-inflammatory agents

“…With this theory, we are reporting the synthesis, characterization and biological evaluation of title compounds for their acute and chronic anti-inflammatory activity as well as their ulcerogenic potential. In this study we have used Autodock 4.2 (Morris et al, 2009) for docking of the synthesized compounds on COX-2 crystal structure (PDB: 3NT1) with (Duggan et al, 2010) binding site which was also previously reported by many authors (Raghavendra et al, 2011, Raghavendra et al, 2013, Basile et al, 2012) Additionally we also have calculated and compared the binding affinities of these compounds with standard reference molecules.…”