Design, synthesis and anti-HIV-1 evaluation of a series of 5-hydroxypyridine-4-one derivatives as possible integrase inhibitors

Rostami, Mahboubeh; Sirous, Hajar; Zabihollahi, Rezvan; Aghasadeghi, Mohammad Reza; Sadat, Seyed Mehdi; Namazi, Rahele; Saghaie, Lotfollah; Memarian, Hamid Reza; Fassihi, Afshin

doi:10.1007/s00044-015-1443-4

Cited by 12 publications

(23 citation statements)

References 39 publications

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“…The molecules selected from in silico combinatorial screening were evaluated using a series of filtering criteria for drug-like properties. In this regard, QikProp application (QikProp, version 3.4, Schrödinger, LLC, New York, NY, 2011) implemented in the Maestro suite was used for ADME-T properties predictions (Rostami et al, 2015; Zaccagnini et al, 2017). This step was performed to select compounds from each library with appropriate physico-chemical properties using the range values recommended by QikProp.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we were particularly interested in taking advantage of the 3-hydroxy-4-pyranone (HP) scaffold for the development of novel HIV-1 INIs due to its application as MBG in the design of several inhibitors of numerous Zn 2+ , Mg 2+ , Mn 2+ , and Cu 2+ dependent proteins. Accordingly, HP derivatives represent an impressive class of heterocyclic ligands with strong bidentate chelating capacity toward metal ions (Santos et al, 2012; Rostami et al, 2015; Sirous et al, 2015). As a first example of the potential of this structural template in HIV-IN inhibition, a series of HP compounds featuring a unique C-2 carboxamide moiety, namely 3-hydroxyl-pyran-4-one-2-carboxamide derivatives (HPCARs), were rationally designed and recently reported by us (Figure 2; Sirous et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

et al. 2019

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We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

et al. 2019

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“…This compound was prepared as previously reported ( 10 11 12 ). To a solution of kojic acid (6.4 g, 0.045 mol) in methanol (70 mL) was added sodium hydroxide (2 g, 0.05 mmol) dissolved in water (5 mL).…”

Section: Methodsmentioning

confidence: 99%

“…The combined organic layers were dried over anhydrous Na 2 SO4, filtered off and evaporated in vacuo to give a light brown solid. Recrystallization from ethanol gave 3a-d as white crystalline solids except for 3e which was an oily compound ( 10 11 12 ).…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands

et al. 2018

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A novel series of antimony (V) complexes with the hydroxypyranone and hydroxypyridinone ligands were synthesized and characterized by 1HNMR, FT-IR and electron spin ionization mass spectroscopic (ESI-MS) techniques. The synthesis process involved protection of hydroxyl group followed by the reaction of the intermediate with primary amines and finally deprotection. All compounds were evaluated for in vitro activities against the amastigote and promastigote forms of Leishmania major. Most of the synthesized compounds exhibited good antileishmanial activity against both forms of L. major. IC50 values of the most active compounds; 9d, 9d and 9e, after 24, 48 and 72 h against amastigote model were 15, 12.5 and 5.5 μg/mL, respectively. 9e, 11 and 9e inhibited the promastigote form of parasite after 24, 48 and 72 h with IC50 values of 10, 2 and 1 μg/mL, respectively.

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Structural aspects of HIV-1 integrase inhibitors: SAR studies and synthetic strategies

Barik,

Gupta,

Singh

et al. 2024

Mol Divers

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Design, synthesis and anti-HIV-1 evaluation of a series of 5-hydroxypyridine-4-one derivatives as possible integrase inhibitors

Cited by 12 publications

References 39 publications

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands

Structural aspects of HIV-1 integrase inhibitors: SAR studies and synthetic strategies

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