General role of the amino and methylsulfamoyl groups in selective cyclooxygenase(COX)-1 inhibition by 1,4-diaryl-1,2,3-triazoles and validation of a predictive pharmacometric PLS model

Perrone, Maria Grazia; Vitale, Paola; Panella, Antonio; Fortuna, Cosimo G.; Scilimati, Antonio

doi:10.1016/j.ejmech.2015.02.049

Cited by 34 publications

(22 citation statements)

References 46 publications

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“…Our discovery of 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) [7] (Fig. 1) as a highly selective COX-1 inhibitor lacking GI toxicity [11] prompted us to attempt in-depth structural modifications of this inhibitor, in order to understand how replacement of chemical moieties affects COX-1 selectivity [5,14–16]. Overall, the selectivity of NSAIDs for COXs remains an open target, mainly due to the similarity between COX isoforms and the complex chemistry of NSAIDs binding to the active site [4,5].…”

Section: Introductionmentioning

confidence: 99%

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cingolani

Panella

Perrone

et al. 2017

European Journal of Medicinal Chemistry

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The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.

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Section: Introductionmentioning

confidence: 99%

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cingolani

Panella

Perrone

et al. 2017

European Journal of Medicinal Chemistry

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“…They are known to possess a wide range of pharmacological activities like anti-microbial, 9,10 anti-inammatory, 11 anti-tubercular, 12 anti-diabetic, 13 anti-malarial, 14 antioxidant, 15 and anti-cancer activities. The basic heterocyclic rings present in various medicinal agents are mainly 1,2,3-triazoles and pyrazoles.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and characterization of new 1,2,3-triazolyl pyrazole derivatives as potential antimicrobial agents via a Vilsmeier–Haack reaction approach

et al. 2016

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The synthesis of a new series of 3-{5-methyl-1-[2-methyl-3-(trifluoromethyl) phenyl/substituted phenyl]-1H-1,2,3-triazol-4-yl}-1-(aryl)-1H-pyrazole-4-carbaldehyde compounds (5a-n) was carried out via a Vilsmeier-Haack formylation of 4-{(1E)-1-[2-(aryl) hydrazinylidene]ethyl}-5-methyl-1-[2-methyl-3-(trifluoromethyl)phenyl/substituted phenyl]-1H-1,2,3-triazole (4a-n) with a phosphorous oxychloride and DMF mixture. The newly synthesized compounds were characterized using IR, 1 H NMR, 13 C NMR, mass spectral data and elemental analysis. The newly synthesized compounds were screened for their in vitro anti-bacterial, anti-fungal and anti-oxidant activities. Some of the synthesized compounds displayed a broad spectrum of antimicrobial activities and moderate to good anti-oxidant activities. The antibacterial results were further supported by in silico molecular docking studies of these compounds for the inhibition of E. coli MurB enzyme (PDB code: 2MBR) and showed a minimum binding energy and good affinity towards the active pocket comparable with the standard drug Ciproflaxin. Thus, they may be considered as good inhibitors of the E. coli MurB enzyme (PDB code: 2MBR).Scheme 1 Synthetic scheme for compounds 5a-n. This journal is

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“…To fasten the lead discovery process, a Volsurf+ (VS+) model was constructed using a dataset of 59 compounds able to predict the in vitro antitumor activity against MCF-7 cancer cell line for the new derivatives. The use of Volsurf+ for in silico models generation is a well established procedure, with proved efficacy [13,14]. Novel compounds when tested in vitro showed a significant agreement with in silico predictions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Experimental Validation of New Designed Heterocyclic Compounds with Antiproliferative Activity versus Breast Cancer Cell Lines MCF-7 and MDA-MB-231

Barresi

Bonaccorso

Cristaldi

et al. 2017

Journal of Chemistry

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Recent drug discovery efforts are highly focused towards identification, design, and synthesis of small molecules as anticancer agents. With this aim, we recently designed and synthesized novel compounds with high efficacy and specificity for the treatment of breast tumors. Based on the obtained results, we constructed a Volsurf+ (VS+) model using a dataset of 59 compounds able to predict the in vitro antitumor activity against MCF-7 cancer cell line for new derivatives. In the present paper, in order to further verify the robustness of this model, we report the results of the projection of more than 150 known molecules and 9 newly synthesized compounds. We predict their activity versus MCF-7 cell line and experimentally verify the in silico results for some promising chosen molecules in two human breast cell lines, MCF-7 and MDA-MB-231.

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General role of the amino and methylsulfamoyl groups in selective cyclooxygenase(COX)-1 inhibition by 1,4-diaryl-1,2,3-triazoles and validation of a predictive pharmacometric PLS model

Cited by 34 publications

References 46 publications

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Design, synthesis and characterization of new 1,2,3-triazolyl pyrazole derivatives as potential antimicrobial agents via a Vilsmeier–Haack reaction approach

Synthesis and Experimental Validation of New Designed Heterocyclic Compounds with Antiproliferative Activity versus Breast Cancer Cell Lines MCF-7 and MDA-MB-231

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