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delavirdine hiv

Wenmin Chen, Peng Zhan, Dirk Daelemans, Jiapei Yang, Boshi Huang, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
Based on the crystallographic studies of diarylpyrimidines (DAPYs), we embarked on incorporating the hydrophilic piperidyl or morpholinyl group into the known DAPY derivatives bearing the pyridine moiety as a core structure, with the double aim to exploit additional interactions with the HIV-1 NNRTI binding pocket (NNIBP), as well as to improve the compound solubility. The antiviral evaluation result show that the most potent compounds I-8b2, I-8b3, I-8b4 and I-8c3 exhibited anti-HIV-1 (IIIB) strain activity ranging from 7...
October 4, 2016: European Journal of Medicinal Chemistry
Sonya Costa, Marisa Machado, Cláudia Cavadas, Maria do Céu Sousa
Co-infection of Leishmaniasis, a neglected tropical disease, with human immunodeficiency virus (HIV) has hindered treatment efficacy. In this study, we aim to evaluate the antileishmanial activity of two protease inhibitors (darunavir and atazanavir) and four reverse transcriptase inhibitors (tenofovir, efavirenz, neviraprine, and delavirdine mesylate) on Leishmania infantum. The activity of different antiretrovirals combinations and of antiretroviral with miltefosine, a drug used on leishmaniasis treatment, was also evaluated...
October 2016: Parasitology Research
Xiao Li, Boshi Huang, Zhongxia Zhou, Ping Gao, Christophe Pannecouque, Dirk Daelemans, Erik De Clercq, Peng Zhan, Xinyong Liu
With the continuation of our unremitting efforts toward the discovery of potent HIV-1 NNRTIs, a series of novel imidazo[4,5-b]pyridin-2-ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure-based drug design. Almost all of the title compounds displayed moderate to good activities against wild-type (wt) HIV-1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell-based antiviral assay. Thereinto, compounds 12 and 13 were the most active two analogues possessing an EC50 value of 0...
August 2016: Chemical Biology & Drug Design
Jiapei Yang, Wenmin Chen, Dongwei Kang, Xueyi Lu, Xiao Li, Zhaoqiang Liu, Boshi Huang, Dirk Daelemans, Christophe Pannecouque, Erik De Clercq, Peng Zhan, Xinyong Liu
The development of novel NNRTIs with activity against variants of HIV-1RT is crucial for overcoming treatment failure. In the present study, a series of novel 6-substituted diarylpyridine derivatives targeting the entrance channel of the NNIBP of RT were designed through a molecular hybridization strategy. Encouragingly, these new diarylpyridine derivatives were found to be active against wild-type (WT) HIV-1 with an EC50 values ranging from 0.035 μM to 1.99 μM. Nearly half of them exhibited more potent inhibitory activities in cellular assays than the control drug nevirapine (NVP)...
February 15, 2016: European Journal of Medicinal Chemistry
Ratsupa Thammaporn, Maho Yagi-Utsumi, Takumi Yamaguchi, Pornthip Boonsri, Patchreenart Saparpakorn, Kiattawee Choowongkomon, Supanna Techasakul, Koichi Kato, Supa Hannongbua
Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is an important target for antiviral therapy against acquired immunodeficiency syndrome. However, the efficiency of available drugs is impaired most typically by drug-resistance mutations in this enzyme. In this study, we applied a nuclear magnetic resonance (NMR) spectroscopic technique to the characterization of the binding of HIV-1 RT to various non-nucleoside reverse transcriptase inhibitors (NNRTIs) with different activities, i.e., nevirapine, delavirdine, efavirenz, dapivirine, etravirine, and rilpivirine...
2015: Scientific Reports
Zheng-Yong Wan, Yuan Tao, Ya-Feng Wang, Tian-Qi Mao, Hong Yin, Fen-Er Chen, Hu-Ri Piao, Erik De Clercq, Dirk Daelemans, Christophe Pannecouque
A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 μM, SI>67) in the anti-HIV-1 in vitro cellular assay...
August 1, 2015: Bioorganic & Medicinal Chemistry
Markus Hecht, Sonja Erber, Thomas Harrer, Hartwig Klinker, Thomas Roth, Hans Parsch, Nora Fiebig, Rainer Fietkau, Luitpold V Distel
BACKGROUND: Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo. METHODS: Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays...
2015: PloS One
Erik De Clercq
Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2',3'-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections...
July 2015: Medicinal Research Reviews
Boshi Huang, Xin Liang, Cuicui Li, Wenmin Chen, Tao Liu, Xiao Li, Yueyue Sun, Lu Fu, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Xinyong Liu
Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0...
March 26, 2015: European Journal of Medicinal Chemistry
Devinder Sharma, Aik Jiang Lau, Matthew A Sherman, Thomas K H Chang
BACKGROUND AND PURPOSE: Rilpivirine and etravirine are second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) indicated for the treatment of HIV/AIDS. The constitutive androstane receptor (CAR) regulates the expression of genes involved in various biological processes, including the transport and biotransformation of drugs. We investigated the effect of rilpivirine and etravirine on the activity of the wild-type human CAR (hCAR-WT) and its hCAR-SV23 and hCAR-SV24 splice variants, and compared it with first-generation NNRTIs (efavirenz, nevirapine, and delavirdine)...
March 2015: British Journal of Pharmacology
Zhaoqiang Liu, Wenmin Chen, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0...
November 24, 2014: European Journal of Medicinal Chemistry
Liu Wang, Ye Tian, Wenmin Chen, Hong Liu, Peng Zhan, Dongyue Li, Huiqing Liu, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were rationally designed via structure-based core refining approach, synthesized through the readily accessible synthetic methods and evaluated for their anti-HIV activities in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against the wild-type HIV-1 IIIB. Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC50 values of 0...
October 6, 2014: European Journal of Medicinal Chemistry
Ye Tian, Deping Du, Diwakar Rai, Liu Wang, Huiqing Liu, Peng Zhan, Erik De Clercq, Christophe Pannecouque, Xinyong Liu
In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07μM against wild-type HIV-1 and very high selectivity index (SI, 3999)...
April 1, 2014: Bioorganic & Medicinal Chemistry
Pru Thein, Gilda M Kalinec, Channy Park, Federico Kalinec
Several studies have reported an increased incidence of auditory dysfunction among HIV/AIDS patients. We used auditory HEI-OC1 cells in cell viability, flow cytometry and caspases 3/7-activation studies to investigate the potential ototoxicity of fourteen HIV antiretroviral agents: Abacavir, AZT, Delavirdine, Didenosine, Efavirenz, Emtricitabine, Indinavir, Lamivudine, Nefinavir, Nevirapine, Tenofovir, Ritonavir, Stavudine and Zalcitabine, as well as combinations of these agents as used in the common anti-HIV cocktails Atripla™, Combivir™, Epzicom™, Trizivir™, and Truvada™...
April 2014: Hearing Research
Iris Usach, Virginia Melis, José-Esteban Peris
INTRODUCTION: Human immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection. DISCUSSION: First-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs...
September 4, 2013: Journal of the International AIDS Society
Hong-Tao Xu, Susan P Colby-Germinario, Wei Huang, Maureen Oliveira, Yingshan Han, Yudong Quan, Christos J Petropoulos, Mark A Wainberg
Resistance to the recently approved nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) commonly involves substitutions at positions E138K and K101E in HIV-1 reverse transcriptase (RT), together with an M184I substitution that is associated with resistance to coutilized emtricitabine (FTC). Previous biochemical and virological studies have shown that compensatory interactions between substitutions E138K and M184I can restore enzyme processivity and the viral replication capacity. Structural modeling studies have also shown that disruption of the salt bridge between K101 and E138 can affect RPV binding...
November 2013: Antimicrobial Agents and Chemotherapy
Shiqiong Yang, Christophe Pannecouque, Dirk Daelemans, Xiao-Dong Ma, Yang Liu, Fen-Er Chen, Erik De Clercq
This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0...
July 2013: European Journal of Medicinal Chemistry
Xuwang Chen, Yuanyuan Li, Shufang Ding, Jan Balzarini, Christophe Pannecouque, Erik De Clercq, Huiqing Liu, Xinyong Liu
In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 ≥146 μM, SI≥14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2...
July 2013: ChemMedChem
Devinder Sharma, Aik Jiang Lau, Matthew A Sherman, Thomas K H Chang
Rilpivirine and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus-1 infection. Pregnane X receptor (PXR) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions. The present study investigated the effects of rilpivirine and etravirine on the activity of human PXR (hPXR), including the mode of activation, and compared them to those of efavirenz, nevirapine, and delavirdine, which are first generation non-nucleoside reverse transcriptase inhibitors...
June 1, 2013: Biochemical Pharmacology
Hussain Syed Iqbal, Sunil Suhas Solomon, Shanmugam Saravanan, Madhavan Vidya, Nagalingeswaran Kumarasamy, Suniti Solomon, Pachamuthu Balakrishnan
CONTEXT: In the era of free HAART, accessibility and availability of ARV has been dramatically increased in India. However, rates of treatment literacy and adherence appear to be sub-optimal. Therefore, it is essential to monitor the extent of primary drug resistance in such settings. MATERIALS AND METHODS: Between July and October 2006, 18 anti-retroviral-naοve individuals were identified as recent infected by the BED-Capture enzyme immunoassay in a VCTC clinic in Chennai...
November 2011: Indian Journal of Medical Sciences
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