4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-Containing Compounds Having High Potency against Raltegravir-Resistant Integrase Mutants of HIV-1

Zhao, Xue Zhi; Smith, Steven J.; Métifiot, Mathieu; Marchand, Christophe; Boyer, Paul L.; Pommier, ﻿Yves; Hughes, Stephen H.; Burke, Terrence R.

doi:10.1021/jm5001908

Cited by 39 publications

(61 citation statements)

References 31 publications

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“…A 2D ligand interaction of molecule 5sS [14] is displayed in Figure 11. It represents the interaction of the molecule with the surrounding amino acids of 1BIS.pdb within an 8-Å radius.…”

Section: Methodsmentioning

confidence: 99%

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Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

Ealy¹,

Abouomar²,

Cogan³

et al. 2017

ABB

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Lipinski's "Rule of Five" was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski's "Rule of Five" was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICMPro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondruglike molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.

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“…A 2D ligand interaction of molecule 5sS [14] is displayed in Figure 11. It represents the interaction of the molecule with the surrounding amino acids of 1BIS.pdb within an 8-Å radius.…”

Section: Methodsmentioning

confidence: 99%

“…Figure 5 and Figure 6 (generated using ICM-Pro, Molsoft L.L.C.) represent an example of a drug-like [14] and nondrug-like molecule [14], respectively. The molecules were docked into the active site of 1BIS.pdb [9] and are shown in the potential binding site pocket identified by ICM-Pro.…”

Section: Drug-like and Nondrug-like Molecules/inhibitorsmentioning

confidence: 99%

Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

Ealy¹,

Abouomar²,

Cogan³

et al. 2017

ABB

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“…Further investigations indicated that incorporation of free amine and alkylamines at the C‐4 position of 2‐naphthyridinone fragment was favorable to the activity, while arylamines were disfavored. The relative contribution order was free amine > alkylamines > arylamines . In particular, compound 6o (EC 50 : 1.1–35 nM) (Figure ) was highly active against IN wt and mutants (Y143R, N155H, R263K, G118R, and G140S/Q148H), and it was 1.4‐64.8 folds more potent than the reference raltegravir against all tested HIV‐1 IN.…”

Section: ‐Quinolone Derivativesmentioning

confidence: 98%

“…Besides IN, RT, and PR are also essential for HIV replication. Therefore, RT and PR have also been used as targets by anti‐HIV therapeutics . 2‐Quinolone derivatives 7 (Figure ) exhibited promising inhibitory activity against wt (IC 50 : 0.24–0.71 µM) and mutant HIV‐1 RT (Cys181 and Il100, IC 50 : 0.86–2.50 µM), which were comparable to nevirapin (IC 50 : 0.30 µM) against wt RT, but >40‐fold more active than nevirapin (IC 50 : > 100 µM) against mutant HIV‐1 Cys181 and Il100 RT .…”

Section: ‐Quinolone Derivativesmentioning

confidence: 99%

Quinolone derivatives: Potential anti‐HIV agent—development and application

Wang

Shi

2019

Archiv der Pharmazie

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“…Zhao et al [91,92] synthesize bicyclic inhibitors having a hydroxyl group at position 1 and 4 in 1, 8-naphthyridine-3-carboxamide scaffolds and evaluate their HIV1 integrase inhibitory activity. Amongst these amides, N-(2,4-difluorophenyl)-1-hydroxyl substituted 1, 8-naphthyridine-3-carboxamide (80a) and N-(2,4-difluorophenyl)-1,4-dihydroxyl substituted 1, 8-naphthyridine-3-carboxamide (80b) show antiviral activity in nanomolar range potencies against HIV-1 integrase.…”

Section: Anti-hiv Activitymentioning

confidence: 99%

Recent Developments and Multiple Biological Activities Available With 1, 8-Naphthyridine Derivatives: A Review

Gurjar¹,

Pal²

2019

Int J Pharm Pharm Sci

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Within the wide range of nitrogen-containing heterocyclic compounds, the derivatives of 1,8-naphthyridine (NPTR) have gained a rising interest due to their reported versatile biological activities. The derivatives of NPTR scaffold are found to invite special interest from researchers nowadays on the significance of their manifestations of multiple attractive pharmacological activities which establish them as an effective and versatile tool in pharmaceutical chemistry and drug discovery. The diverse biological activities mainly include anti-inflammatory, antimicrobial, antiviral, anticancer, antihypertensive and analgesic activities. Novel NPTR scaffold has emerged its potency to treat neurological diseases like depression and Alzheimer's disease. Further these agents possess different inhibitory activities, such as anti-HIV, anti-osteoporotic, αvβ3 antagonism, antimalarial, platelet aggregation, anti-oxidant, anti-allergic, gastric antisecretory, anticonvulsant, epidermal growth factor receptor (EGFR) inhibition, protein kinase inhibition, ionotropic properties, β3 antagonism, phosphodiesterase 4 (PDE 4) inhibitions, adenosine receptor agonistic activity, adrenoceptors antagonism and DNA stabilizing activity, etc. In this review, we highlight the updates of different 1,8-naphthyridine derivatives and explain the key data available in the context of various biological activities of NPTR derivatives available from the literature. This may direct opportunity in researches in the synthesis of novel medicinal agents and the development of new heterocycles for modification of existing biological actions as well as evaluation of other possible pharmacological activities.

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4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-Containing Compounds Having High Potency against Raltegravir-Resistant Integrase Mutants of HIV-1

Cited by 39 publications

References 31 publications

Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

Quinolone derivatives: Potential anti‐HIV agent—development and application

Recent Developments and Multiple Biological Activities Available With 1, 8-Naphthyridine Derivatives: A Review

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