Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands

Sancineto, Luca; Iraci, Nunzio; Barreca, Maria Letizia; Massari, Serena; Manfroni, Giuseppe; Corazza, Gianmarco; Cecchetti, Violetta; Marcello, Alessandro; Daelemans, Dirk; Pannecouque, Christophe; Tabarrini, Oriana

doi:10.1016/j.bmc.2014.07.018

Cited by 21 publications

(9 citation statements)

References 36 publications

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“…Automated molecular docking of rutin into Mpro active site was carried out using Glide [ 43 , 44 , 45 ]. Docking target structure (PDB 7L11) [ 40 ] was prepared as previously described [ 46 , 47 ], using the Schrodinger protein preparation utility [ 48 ]. Docking space was centered on the native ligand of 7L11 and defined as a 25 Å 3 cubic box, constraining the ligand diameter midpoint into a nested 20 Å 3 cubic box.…”

Section: Methodsmentioning

confidence: 99%

l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells

et al. 2021

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The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with L-arginine. Tests of the rutin/L-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization.

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Section: Methodsmentioning

confidence: 99%

l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells

et al. 2021

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“…It was merged with donepenzil in order to obtain multi-target-directed ligands (MTDL) capable of inhibiting both cholinesterases and oxidative stress simultaneously [ 132 ]. The synthesis of MTDL, also known as designed multiple ligands [ 133 ], is a new avenue in medicinal chemistry used not only in AD but also in several other research fields [ 134 , 135 , 136 ]. Recently, the benzisoselenazolone scaffold was merged with clioquinol, a compound known for its ability to chelate metals and inhibit Aβ deposits.…”

Section: Anti-neurodegenerative Disordersmentioning

confidence: 99%

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation

2021

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Ebselen is the leader of selenorganic compounds, and starting from its identification as mimetic of the key antioxidant enzyme glutathione peroxidase, several papers have appeared in literature claiming its biological activities. It was the subject of several clinical trials and it is currently in clinical evaluation for the treatment of COVID-19 patients. Given our interest in the synthesis and pharmacological evaluation of selenorganic derivatives with this review, we aimed to collect all the papers focused on the biological evaluation of ebselen and its close analogues, covering the timeline between 2016 and most of 2021. Our analysis evidences that, even if it lacks specificity when tested in vitro, being able to bind to every reactive cysteine, it proved to be always well tolerated in vivo, exerting no sign of toxicity whatever the administered doses. Besides, looking at the literature, we realized that no review article dealing with the synthetic approaches for the construction of the benzo[d][1,2]-selenazol-3(2H)-one scaffold is available; thus, a section of the present review article is completely devoted to this specific topic.

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“…The target diketoquinolines 1-14 were prepared from the commercially procured intermediates such as methyl-7-chloro-1-cyclopropyl-6fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate, methyl-7-chloro-1-ethyl-6-fluoro-1, 4-dihydro-4oxo Quinoline-3-carboxylate and 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7-(piperazin-1-yl) quinoline-3carboxylate [21][22][23][24][25][26] . The fabricated way is marked in Scheme 1.…”

Section: Chemistrymentioning

confidence: 99%

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2020

IJPSR

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A progression of fourteen narrative quinolonyl diketo acid analogs were planned, synthesized, identified by IR, NMR, CHN and MS supernatural analysis and evaluated as potential HIV-1 Integrase hinders. Compounds of Zinc database were surfed considering Elvitegravir as standard. Nearly 99 compounds were identified and docked in the active site of HIV-1 integrase. Molecular docking study of compounds 1, 4 and 7 showed docking score -10.38, -9.31 and -10.12 respectively as that of set drug Elvitegravir -4.93. The docking poses to open the interaction of the ligands with preferred amino acids. The standard drug Elvitegravir displayed connections with lys156, Asn155, Lys159 and Thr66. Raltegravir showed hydrogen bonding with Asp 116. A round fourteen target diketoquinolines were chosen for advance synthesis with the help of substituted oxoquinoline-3-carboxylate as starting material. Invitro biological evaluation open that some of the upper-class compounds exhibited moderate to good inhibitory activity besides HIV1 Integrase compared to the reference drugs Raltegravir and Nevirapine. Compounds 1, 2, 3 and 4 weakly inhibited HIV-1 integrase at EC50 of 0.31, 0.25, 0.22 & 0.21 with the therapeutic index 242, 260, 266 and 278 respectively. The cytotoxicity of upperclass compounds on C8166 cells was very low, the CC50 value was higher than 200 μM, except for few compounds. As an optimistic control drug, Nevirapine showed significant anti-HIV-1 activity (EC50 = 0.015~0.016 μM) in-vitro, and the CC50 was higher than 200 μM, with a therapeutic index value of 12418.50. Compound 14 exhibited significant inhibition of HIV-1 syncytium and integrase at EC50 0.25 and 0.12 respectively.

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Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands

Cited by 21 publications

References 36 publications

l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells

l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation

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