Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

Choi, Eungi; Mallareddy, Jayapal Reddy; Lu, Dai; Kolluru, Srikanth

doi:10.4155/fsoa-2018-0060

Cited by 40 publications

(63 citation statements)

References 139 publications

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“…In the same way, ring extension at the nitrogen of piperazine was carried out by substituted benzoic acid. The ester linkage in intermediate compound (COOCH3) is hydrolyzed to a carboxylic acid (COOH) in an alkaline medium in the attendance of melted lithium hydroxide to yield the target compounds [1][2][3][4][5][6][7][8][9][10][11][12][13][14] .…”

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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Section: Chemistrymentioning

confidence: 99%

“…HIV-1 IN process the integration of viral genetic material with the host genome, a key step in the viral duplication process. Several novel classes of HIV IN inhibitors have been explored by targeting different sites on the enzyme 3,4 .…”

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confidence: 99%

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2020

IJPSR

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“…Designing and development of small molecule‐based antimicrobial agents is the need of the day as the microbial disease threat and drug resistance of microbes getting increased. Advanced bioinformatics and biotechnological applications and relevant developments are boosting the discovery and development of small‐molecule drugs effectively . These biologically active compound screening measures are favoring in choosy and effective medicinal agents towards many diseases with agreeable or lesser side effects.…”

Section: Introductionmentioning

confidence: 99%

“…Advanced bioinformatics and biotechnological applications and relevant developments are boosting the discovery and development of small-molecule drugs effectively. [1,2] These biologically active compound screening measures are favoring in choosy and effective medicinal agents towards many diseases with agreeable or lesser side effects. Among a number of small molecules, quinoline-based compounds are getting their attraction in drug designing research studies due to their drug efficacy against a wide range of diseases.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological activities of nitro‐hydroxy‐phenylquinolines; validation of antibiotics effect over DNA gyrase inhibition and antimicrobial activity

Bilavendran

Thangarasu

Sivakumar³

2020

Journal of Heterocyclic Chem

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A family of 11 nitrophenol 2‐nitro‐5‐(4‐substituted phenylquinolin‐2‐yl)phenol derivatives (4, 4a‐j) was effectively synthesized as antimicrobial medications. A mixture of the substituted 3‐hydroxy‐4‐nitrobenzaldehyde substituted aromatic amine and substituted phenylacetylenes were used to synthesis the title compounds 4, 4a‐j. Antimicrobialactivity potential of 4, 4a‐j was evaluated against Streptococcus pyogenes (MTCC 442), Staphylococcus aureus (MTCC 96), Pseudomonas aeruginosa (MTCC 424), and Escherichia coli (MTCC 443). DNA gyrase inhibition studies carried out to understand the mechanism ofaction of the antimicrobial effect of target compounds. HRBC membrane stabilization (in vitro) property was also assessed as a representative human cellular cytotoxic effect of 4, 4a‐j since HRBC alike lysosomal cells and the lysozyme activity leads to inflammation and its adverse effects in cellular systems. Results reveal that compounds 4c and 4h have remarkable antibacterial activity and screened for further preclinical studies.

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“…In addition, a number of triterpene derivatives, caffeoylquinic acid derivatives, and flavonoids have exhibited potent inhibitory effects against human immunodeficiency virus (HIV)-1 integrase and prevented HIV-1 replication in tissue culture [15][16][17][18][19]. However, in vitro binding and inhibition of HIV-1 integrase does not always translate into potency against HIV replication [20,21]. In this study, we isolated and characterized nine compounds from the acid hydrolysate of the flower buds of L. fulvotomentosa Hsu et S. C. Cheng and evaluated their respective anti-HIV-protease activity under in vitro conditions, aiming to verify whether inhibition of HIV protease is also involved in the anti-HIV function of Lonicera species.…”

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Characterization of Nine Compounds Isolated from the Acid Hydrolysate of Lonicera fulvotomentosa Hsu et S. C. Cheng and Evaluation of Their In Vitro Activity towards HIV Protease

et al. 2019

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In this study, we isolated nine compounds from the acid hydrolysate of the flower buds of Lonicera fulvotomentosa Hsu et S. C. Cheng and characterized their chemical structures using 1 H-NMR, 13 C-NMR, and electron ionization mass spectroscopy (EI-MS). These compounds were identified as β-sitosterol (1), 5,5 -dibutoxy-2,2 -bifuran (2), nonacosane-10-ol (3), ethyl (3β)-3,23-dihydroxyolean-12-en-28-oate (4), oleanolic acid (5), ethyl caffeate (6), caffeic acid (7), isovanillin (8), and hederagenin (9), with 4 as a new triterpene compound. Inhibitory activity against human immunodeficiency virus (HIV) protease was also evaluated for the compounds, and only ethyl caffeate, caffeic acid, and isovanillin (6, 7, and 8) exhibited inhibitory effects, with IC 50 values of 1.0 µM, 1.5 µM, and 3.5 µM, respectively. Molecular docking with energy minimization and subsequent molecular dynamic (MD) simulation showed that ethyl caffeate and caffeic acid bound to the active site of HIV protease, while isovanillin drifted out from the active site and dissociated into bulk water during MD simulations, and most of the binding residues of HIV protease have been previously identified for HIV protease inhibitors. These results suggest that caffeic acid derivatives may possess inhibitory activities towards HIV protease other than previously reported inhibitory activities against HIV integrase, and thus ethyl caffeate and caffeic acid could be used as lead compounds in developing potential HIV protease inhibitors, and possibly even dual-function inhibitors against HIV.

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Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

Cited by 40 publications

References 139 publications

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Untitled

Synthesis and biological activities of nitro‐hydroxy‐phenylquinolines; validation of antibiotics effect over DNA gyrase inhibition and antimicrobial activity

Characterization of Nine Compounds Isolated from the Acid Hydrolysate of Lonicera fulvotomentosa Hsu et S. C. Cheng and Evaluation of Their In Vitro Activity towards HIV Protease

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