Synthesis, characterization and molecular docking of novel lonazolac analogues 3-(3-hydroxy-5-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives: Highly potential COX-1/COX-2, matrix metalloproteinase and protein denaturation inhibitors

Pawar, Varsha; Shastri, Lokesh A.; Gudimani, Parashuram; Joshi, Shrinivas D.; Sunagar, Vinay A.

doi:10.1016/j.molstruc.2022.132782

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…Furthermore, diaza-1,3-dienes 78 with N -substituted phenyl ring with disubstitution also tolerated this protocol regardless of its relative positions. Furthermore, the research group also illustrated the synthetic utility of this protocol by producing analogs of the drugs lonazolac 72 (anti-inflammatory drug) and rimonabant 73 (antiobesity drug).…”

Section: Classificationmentioning

confidence: 99%

Silver-catalyzed synthesis of nitrogen heterocycles: recent advancements

2023

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Section: Classificationmentioning

confidence: 99%

Silver-catalyzed synthesis of nitrogen heterocycles: recent advancements

2023

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“…Novel compounds have been designed to target the COX-1 [12], especially in tumor cells and tissues where it is overexpressed [13][14][15][16][17]. From a chemical viewpoint, the molecules must carry at least three moieties: a mofezolac unit recognized through its carboxylic group by COX amino acid residues (Arg120, Tyr355, and Glu524) located at the entrance of the enzyme long hydrophobic channel that has the catalytic site on its top [18], a linker and a fluorochrome.…”

Section: Rationale Behind the Design Of The Novel Target Compoundsmentioning

confidence: 99%

Fluorochrome Selection for Imaging Intraoperative Ovarian Cancer Probes

et al. 2022

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The identification and removal of all gross and microscopic tumor to render the patient disease free represents a huge challenge in ovarian cancer treatment. The presence of residual disease is an independent negative prognostic factor. Herein, we describe the synthesis and the “in vitro” evaluation of compounds as cyclooxygenase (COX)-1 inhibitors, the COX-1 isoform being an ovarian cancer biomarker, each bearing fluorochromes with different fluorescence features. Two of these compounds N-[4-(9-dimethylimino-9H-benzo[a]phenoxazin-5-ylamino) butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (RR11) and 3-(6-(4-(2-(3,4-bis(4-methoxyphenyl)isoxazole-5-yl)acetamido)butyl)amino-6-oxohexyl)-2-[7-(1,3-dihydro-1,1-dimethyl-3-ethyl 2H-benz[e]indolin-2-yl-idene)-1,3,5-heptatrienyl]-1,1-dimethyl-3-(6-carboxilato-hexyl)-1H-benz[e]indolium chloride, 23 (MSA14) were found to be potent and selective inhibitors of cyclooxygenase (COX)-1 “in vitro”, and thus were further investigated “in vivo”. The IC50 values were 0.032 and 0.087 µM for RR11 and 23 (MSA 14), respectively, whereas the COX-2 IC50 for RR11 is 2.4 µM while 23 (MSA14) did not inhibit COX-2 even at a 50 µM concentration. Together, this represented selectivity index = 75 and 874, respectively. Structure-based virtual screening (SBVS) performed with the Fingerprints for Ligands and Proteins (FLAP) software allowed both to differentiate highly active compounds from less active and inactive structures and to define their interactions inside the substrate-binding cavity of hCOX1. Fluorescent probes RR11 and 23 (MSA14), were used for preliminary near-infrared (NIR) fluorescent imaging (FLI) in human ovarian cancer (OVCAR-3 and SKOV-3) xenograft models. Surprisingly, a tumor-specific signal was observed for both tested fluorescent probes, even though this signal is not linked to the presence of COX-1.

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“…The history of the medical use of 4-unsubstituted pyrazolinones began as early as 1887 with the discovery of antipyrine (1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one), one of the first nonopioid analgesics and antipyretics. This discovery prompted the study of pyrazolone derivatives, including C4-monosubstituted pyrazolones, pyrazolone-based Schiff bases, and their metal complexes, which possess anti-inflammatory, antipyretic and analgesic [22,[25][26][27], antitumor/cytotoxic [22,25,[28][29][30], antimicrobial [22,25,[31][32][33], antioxidant [22,26], and protein denaturation inhibiting [27] activities. The interest of medicinal chemists to pyrazolones has been maintained and is increasing at the present time [22].…”

Section: Introductionmentioning

confidence: 99%

4-Disubstituted Pyrazolin-3-Ones—Novel Class of Fungicides against Phytopathogenic Fungi

et al. 2023

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The search for fungicides of novel classes is the long-standing priority in crop protection due to the continuous development of fungal resistance against currently used types of active compounds. Recently, 4-nitropyrazolin-3-ones were discovered as highly potent fungicides, of which activity was believed to be strongly associated with the presence of a nitro group in the pyrazolone ring. In this paper, a series of 4-substituted pyrazolin-3-ones were synthesized and their fungicidal activity against an important species of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum) was tested in vitro. We discovered that 4-mono and 4,4-dihalogenated pyrazolin-3-ones demonstrate fungicidal activity comparable to that of 4-nitropyrazolin-3-ones and other modern fungicides (such as kresoxim methyl). This discovery indicates that NO2 moiety can be replaced by other groups of comparable size and electronic properties without the loss of fungicidal activity and significantly expands the scope of potent new fungicides based on a pyrazolin-3-one fragment.

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Synthesis, characterization and molecular docking of novel lonazolac analogues 3-(3-hydroxy-5-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives: Highly potential COX-1/COX-2, matrix metalloproteinase and protein denaturation inhibitors

Cited by 8 publications

References 41 publications

Silver-catalyzed synthesis of nitrogen heterocycles: recent advancements

Silver-catalyzed synthesis of nitrogen heterocycles: recent advancements

Fluorochrome Selection for Imaging Intraoperative Ovarian Cancer Probes

4-Disubstituted Pyrazolin-3-Ones—Novel Class of Fungicides against Phytopathogenic Fungi

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