Use of the Kohonen Neural Network for Rapid Screening of Ex Vivo Anti-HIV Activity of Styrylquinolines

Polański, Jarosław; Zouhiri, Fatima; Jeanson, Laurence; Desmaële, Didier; d’Angelo, Jean; Mouscadet, Jean‐François; Gieleciak, Rafał; Gasteiger, Johann; Bret, Marc Le

doi:10.1021/jm020845g

Cited by 93 publications

(73 citation statements)

References 30 publications

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“…KHD161, FZ55 and FZ117 (Fig. 1) were synthesized as described previously Polanski et al, 2002). Oligonucleotides U5B, 5Ј-GTGTG-GAAAATCTCTAGCAGT-3Ј; U5B-2, 5Ј-GTGTGGAAAATCTCTAGCA-3Ј; U5A, 5Ј-ACTGCTAGAGATTTTCCACAC-3Ј; U5B-F, 5Ј-F-GTGTG-GAAAATCTCTAGCAGT-3Ј (where F designates the fluorescein probe); LDS32Bp, 5Ј-p-ACCCTTTTAGTCAGTGTGGAAAATCTCTAGCA-3Ј; LDS31A, 5Ј-ACTGCTAGAGATTTTCCACACTGACTAAAAG-3Ј; T1A, 5Ј-AGTGAATTAGCCCTTGGTCA-biotin; and T1B, 5Ј-TGAC-CAAGGGCTAATTCACT-biotin were purchased from Eurogentec (Seraing, Belgium) and further purified on an 18% denaturing acrylamide/ urea gel.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Deprez¹,

Barbe²,

Kolaski³

et al. 2004

Mol Pharmacol

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Styrylquinoline derivatives (SQ) efficiently inhibit the 3Ј-processing activity of integrase (IN) with IC 50 values of between 0.5 and 5 M. We studied the mechanism of action of these compounds in vitro. First, we used steady-state fluorescence anisotropy to assay the effects of the SQ derivatives on the formation of IN-viral DNA complexes independently of the catalytic process. The IC 50 values obtained in activity and DNAbinding tests were similar, suggesting that the inhibition of 3Ј-processing can be fully explained by the prevention of IN-DNA recognition. SQ compounds act in a competitive manner, with K i values of between 400 and 900 nM. In contrast, SQs did not inhibit 3Ј-processing when IN-DNA complexes were preassembled. Computational docking followed or not by molecular dynamics using the catalytic core of HIV-1 IN suggested a competitive inhibition mechanism, which is consistent with our previous data obtained with the corresponding Rous sarcoma virus domain. Second, we used preassembled IN-preprocessed DNA complexes to assay the potency of SQs against the strand transfer reaction, independently of 3Ј-processing. Inhibition occurred even if the efficiency was decreased by about 5-to 10-fold. Our results suggest that two inhibitorbinding modes exist: the first one prevents the binding of the viral DNA and then the two subsequent reactions (i.e., 3Ј-processing and strand transfer), whereas the second one prevents the binding of target DNA, thus inhibiting strand transfer. SQ derivatives have a higher affinity for the first site, in contrast to that observed for the diketo acids, which preferentially bind to the second one.Integration of the HIV-1 DNA into the host genome ensures stable maintenance of the viral genome and perpetuation of the virus in the host organism. Therefore, this reaction, catalyzed by integrase (IN), is a key process in the life cycle of the virus. Inhibitors of therapeutic interest for AIDS exist. Inhibitors that act early in the replication cycle target reverse transcriptase and those that act later target protease. The high mutation rate of HIV means that drug resistance is emerging, making it necessary to develop new drugs with different targets (combined therapies). Thus, it is essential to find drugs that target alternative steps of the HIV-1 replication cycle. IN, the third enzyme of the Pol precursor protein, is then an attractive target for novel drugs because of its central role in the HIV-1 life cycle.IN is a 32-kDa protein (288 amino acids) that consists of three functional domains. The central domain (or core domain, residues 50 -210) contains the catalytic triad (DDE) that is essential for enzymatic activity. This domain is flanked by the N-terminal domain (which has a role in the assembly of an active multimeric form of the enzyme) and the C-terminal domain (which has a role in the nonspecific DNAbinding activity). These three domains, protein oligomerization, the integrity of the catalytic triad, and a cationic cofactor such as magnesium are all necessary fo...

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Section: Methodsmentioning

confidence: 99%

Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Deprez¹,

Barbe²,

Kolaski³

et al. 2004

Mol Pharmacol

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“…Similarly, bromination of the C-5 position and protection of the salicylic moiety provided 5-bromoquinaldine compound 2, which was engaged in a modified Suzuki cross-coupling reaction to give 5-arylated derivatives 14 to 16 (19). Styrylquinoline compounds 19 to 27 were prepared from the corresponding quinaldine compound 3 by Perkin-type condensation in refluxing acetic anhydride, followed by hydrolysis in a pyridine-water mixture (10,16,21,22). Finally, the 7-aroyl-stryryquinoline derivatives 28 to 35 were obtained via the 7-bromostyrylquinoline compound 5 according to a threestep sequence involving lithiation followed by condensation with the required aldehyde, manganese dioxide oxidation, and deprotection (15) (Fig.…”

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confidence: 99%

In Vitro Activities of New 2-Substituted Quinolines against Leishmania donovani

Loiseau

Gupta

Verma

et al. 2011

Antimicrob Agents Chemother

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A series of 9 quinolines and 18 styrylquinolines was evaluated for the drugs' in vitro antileishmanial activities and cytotoxicities. The 7-aroylstyrylquinoline scaffold appeared to be the most promising one, with the most interesting compound, no. 35, exhibiting a 50% inhibitory concentration (IC 50 ) of 1.2 M and a selectivity index value of 121.5. Compound 35 was 10-fold and 8-fold more active than miltefosine and sitamaquine, the reference compounds, with selectivity indexes 607-fold and 60-fold higher, respectively.Leishmaniasis is a family of parasitic diseases that affect about 12 million people in tropical and subtropical areas in the form of three clinical expressions: visceral leishmaniasis, which is fatal in the absence of treatment; muco-cutaneous leishmaniasis; and cutaneous leishmaniasis, which is often selfcuring. Classical drugs such as antimonials (Pentostam and Glucantime) are toxic, and drug resistance is increasing dangerously in the field (3). A liposomal amphotericin B formulation (AmBisome) less toxic than amphotericin B deoxycholate is gradually becoming the first-line therapy, especially in immunocompromised patients, but this drug must be administered by a parenteral route (11). Miltefosine (Impavido) was the first drug registered against visceral leishmaniasis in the last decade; however, its toxicity and the appearance of drug resistance justify the search for new chemical series in order to find an orally safe and active drug (8).Quinolines substituted at the 2-position have shown in vivo activities against Leishmania donovani, and many compounds have been synthesized over the last decade (14). The Drug for Neglected Diseases Initiative (DNDi) has been considering this series for evaluation in preclinical development for about a year and a half. However, although promising, the series still requires improvements, and here we report the in vitro antileishmanial evaluation of new quinoline derivatives, including 2-[2-aryl(ethenyl)]-substituted quinoline (2-styrylquinolines) bearing additional aroyl/acyl groups at the C-7 position. In addition, some compounds within this series were recently shown to display substantial antiviral activity in HIV-infected cells (13,22).The synthesis of most of the compounds has been previously reported. Briefly, Kolbe carbonation of 8-hydroxyquinaldine afforded the pivotal hydroxyacid compound 1 (9), which was further elaborated into the 5-iodoquinaldine compound 12 and amide compound 17 (13). Similarly, bromination of the C-5 position and protection of the salicylic moiety provided 5-bromoquinaldine compound 2, which was engaged in a modified Suzuki cross-coupling reaction to give 5-arylated derivatives 14 to 16 (19). Styrylquinoline compounds 19 to 27 were prepared from the corresponding quinaldine compound 3 by Perkin-type condensation in refluxing acetic anhydride, followed by hydrolysis in a pyridine-water mixture (10,16,21,22). Finally, the 7-aroyl-stryryquinoline derivatives 28 to 35 were obtained via the 7-bromostyrylquinoline compound 5 accordin...

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“…The return of tuberculosis was declared by World Health Organization (WHO) as a global emergency compared to a hypothetic third world war with 9 million new TB cases and two million deaths reported each year 2,3 ; about one-third of the world's population is already infected with M. tuberculosis 4 . The quinoline was reported to exhibit various biological activity such as antiviral 5,6 , antiamoebic 7 , anti-inflammatory 8,9 as well as antimalarial 10,11 activity. In addition, the discovery of nalidixic acid, a urinary tract antimicrobial drug 12 , prompted the synthesis of many quinoline derivatives and evaluationfor their antimicrobial activity [13][14][15] and antibacterial activity.…”

Section: Tuberculosis (Tb) Is a Global Epidemic Caused By Various Strmentioning

confidence: 99%

Synthesis, Characterization and Biological Evaluation of 6-Substituted-2-(Substituted-Phenyl)-Quinoline Derivatives Bearing 4-Amino-1,2,4-Triazole-3-Thiol Ring at C-4 Position

Vaghasiya

Ghodasara

Vachharajani

et al. 2014

ILCPA

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Quinoline derivatives represent one of the most active classes of compounds possesses wide spectrum biodynamic activities and use as potent therapeutic agents. In this research work, a synthesis, characterization and biological evaluation of 6-substituted-2-(substituted-phenyl)-quinoline derivatives bearing 4-amino-1,2,4-triazole-3-thiol ring at C-4 position is described. The synthesis of quinoline derivatives is carried out by the reaction of substituted quinoline-4-carbohydrazides with a mixture of carbon disulphide and potassium hydroxide which further react with hydrazine hydrate to give final compounds. All of these compounds were screened for their in vitro antimicrobial assay against gram (+ve), gram (-ve) bacteria and fungi activity compared with standard drugs viz., Ampicilin, Chloramphenicol, Ciprofloxacin, Norfloxacin, Griseofulvin and Nystatin at different concentrations.

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Use of the Kohonen Neural Network for Rapid Screening of Ex Vivo Anti-HIV Activity of Styrylquinolines

Cited by 93 publications

References 30 publications

Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

In Vitro Activities of New 2-Substituted Quinolines against Leishmania donovani

Synthesis, Characterization and Biological Evaluation of 6-Substituted-2-(Substituted-Phenyl)-Quinoline Derivatives Bearing 4-Amino-1,2,4-Triazole-3-Thiol Ring at C-4 Position

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