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PubMed1999

Non-nucleoside reverse transcriptase inhibitors: the NNRTI boom.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are promising drugs for the treatment of HIV when used in combination with other anti-HIV drugs such as nucleoside reverse transcriptase (RT) inhibitors and protease inhibitors. The first generation of NNRTIs have, however, suffered from the rapid development of resistance. This review discusses the properties of the FDA-approved NNRTI drugs and focuses on the recent efforts being made to produce second generation inhibitors that circumvent this resistance problem.

Animals↗
PubMed2002

Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1.

The relative potency and tolerability of multidrug regimens used to treat infants and children infected with human immunodeficiency virus type 1 (HIV-1) are largely unknown. In Pediatric AIDS Clinical Trials Group (PACTG) Protocol 377, 181 infants and children were assigned to receive stavudine (d4T) plus nevirapine (NVP) and ritonavir (RTV); d4T plus lamivudine (3TC) and nelfinavir (NFV); d4T plus NVP and NFV; or d4T plus 3TC, NVP, and NFV. Eleven additional children received d4T and NVP plus NFV given twice daily. All subjects had not previously received protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and all had been immunologically stable while receiving reverse-transcriptase inhibitor therapy. After 48 weeks of therapy, 17 (41%) of 41 subjects receiving d4T-NVP-RTV, 13 (30%) of 44 receiving d4T-NVP-NFV, 21 (42%) of 50 receiving d4T-3TC and NFV (3 times daily), and 22 (52%) of 42 receiving d4T-3TC-NVP-NFV were still receiving their assigned therapy and had HIV-1 RNA suppression to </= 400 copies/mL. These regimens were similar in their drug activity, but the 4-drug regimen offered slightly more durable suppression of viremia.

Anti-HIV Agents↗
PubMed2004

The role of nucleoside and nucleotide reverse transcriptase inhibitor backbones in antiretroviral therapy.

Several dual nucleoside reverse transcriptase inhibitor (NRTI) combinations provide efficacy when combined with a 3rd agent. However, there are a number of issues with current NRTI and nucleotide reverse transcriptase inhibitor (NtRTI) combinations that often lead to treatment failure and limited treatment options. These issues include suboptimal potency, drug interactions, toxicities, tolerability issues, and selection of resistance mutations that confer cross-resistance. Options for simplified NRTI backbones include fixed-dose combinations and agents that allow once-daily dosing; however, once-daily treatment choices are currently limited because of a lack of data on potential combinations. This article provides an historical perspective on the use of NRTI backbones in the treatment of HIV infection and outlines the advantages and disadvantages of currently available backbone combinations. In addition, it provides a brief introduction to backbone combinations under investigation as potential options for initial therapy. In an environment where several NRTI/NtRTI backbones offer comparable efficacy, treatment decisions will increasingly be made based on toxicity, resistance, and convenience considerations.

Anti-HIV Agents↗
PubMed1998

Colorimetric assays for evaluation of the mode of action of human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors.

Four non-nucleoside reverse transcriptase (RT) inhibitors, 9-CI-TIBO [(+)-S-4,5,6,7-tetrahydro-9- chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo(4,5,1-jk)(1,4)- benzodiazepin-2(1H)-thione)], nevirapine (6,11-dihydro-11-cyclopropyl-4-methyl-dipyrido[2,3-b:2',3'-e]-[1,4]di azepin- 6-one), MSA-300 (N-[cis-2-(2-hydroxy-3-acetyl-6-methoxy-phenyl)-cyclopropyl]-N'- (5-chloropyrid-2-yl)-thiourea) and delavirdine ¿1-(5-methanesulphonamido-1H-indol-2-yl-carbonyl)-4-[3- (1-methylethylamino)pyridinyl]piperazine¿ were analysed for the mode of action of their inhibition of human immunodeficiency virus type 1 (HIV-1) RT in three different assays utilizing a 96-well microtitre plate format, with solid-phase conjugated poly(rA) as template. These were: (i) direct RT assay, for determination of IC50 values of RT inhibitors; (ii) RT template/primer binding inhibition (BIC) assay, for measuring the effect of various substances on the RT activity binding to template/primer; (iii) RT protein ELISA, for measuring RT protein binding to template/primer with a monoclonal antibody reactive against a peptide in the RNase H region. MSA-300 and delavirdine gave the lowest IC50 values, ranging from 0.17 microM to 0.24 microM for MSA-300 and from 0.12 microM to 0.38 microM for delavirdine, whereas higher IC50 values of approximately 20 microM were obtained for 9-CI-TIBO at all primer concentrations. None of the non-nucleoside substances had inhibiting effects on the binding of template, primer, or template/primer to RT protein. Their inhibition of RT activity was not due to prevention of RT binding to template/primer. TIBO, nevirapine and delavirdine bound to RT reversibly, and they bound more tightly to RT template/primer ternary than to RT template binary complex. MSA-300 showed a comparatively high affinity for the enzyme. The utility of the three assays in relation to screening and analysis of RT inhibitory substances is discussed.

Amino Acid Sequence↗
PubMed2000

Determination of nevirapine, an HIV-1 non-nucleoside reverse transcriptase inhibitor, in human plasma by reversed-phase high-performance liquid chromatography.

A sensitive and rapid high-performance liquid chromatography method has been developed to measure the levels of the HIV-1 non-nucleoside reverse transcriptase inhibitor nevirapine in human plasma. The sample pre-treatment consists of a protein precipitation with perchloric acid. A Hypersil ODS column is used at ambient temperature and a wavelength of 280 nm is used for ultraviolet detection. The mobile phase contains acetonitrile and a 60 mM phosphate buffer pH 4.5 (30:70, v/v). The detection limit of the method is 0.05 mg/l using 150 microl of plasma. The lower and upper limit of quantitation are 0.1 mg/l and 10 mg/l, respectively. The average recovery of nevirapine is 101.8% with a variation of 4.6%. The average inter-assay precision is 2.4%, the average intra-assay precision 2.9% and the average accuracy 97%.

Adult↗
PubMed2005

Letter. In vitro phenotypic susceptibility to nucleoside reverse transcriptase inhibitors of HIV-2 isolates with the Q151M mutation in the reverse transcriptase gene.

In HIV-2 infection, many studies have reported a high frequency of selection of the Q151M mutation, but its impact on phenotypic susceptibility of HIV-2 isolates remains unclear. Four HIV-2 infected patients from the French ANRS HIV-2 cohort, with evidence of Q151M mutation in both plasma and available peripheral blood mononuclear cells (PBMCs) co-cultivated supernatants, were selected. In vitro phenotypic susceptibilities to different nucleoside reverse transcriptase inhibitors (NRTIs) were determined using a PBMC assay. In HIV-2 isolates, the Q151M mutation alone impacts only the phenotypic susceptibility to stavudine and abacavir. A decrease in susceptibility to all NRTIs was observed when Q151M was selected with V111I, a mutation of unknown impact on HIV-1 resistance. Clinical relevance of these phenotypic susceptibility results needs to be evaluated in HIV-2 treated patients.

Drug Resistance, Multiple, Viral↗
PubMed2006

Potent nonnucleoside reverse transcriptase inhibitors target HIV-1 Gag-Pol.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) target HIV-1 reverse transcriptase (RT) by binding to a pocket in RT that is close to, but distinct, from the DNA polymerase active site and prevent the synthesis of viral cDNA. NNRTIs, in particular, those that are potent inhibitors of RT polymerase activity, can also act as chemical enhancers of the enzyme's inter-subunit interactions. However, the consequences of this chemical enhancement effect on HIV-1 replication are not understood. Here, we show that the potent NNRTIs efavirenz, TMC120, and TMC125, but not nevirapine or delavirdine, inhibit the late stages of HIV-1 replication. These potent NNRTIs enhanced the intracellular processing of Gag and Gag-Pol polyproteins, and this was associated with a decrease in viral particle production from HIV-1-transfected cells. The increased polyprotein processing is consistent with premature activation of the HIV-1 protease by NNRTI-enhanced Gag-Pol multimerization through the embedded RT sequence. These findings support the view that Gag-Pol multimerization is an important step in viral assembly and demonstrate that regulation of Gag-Pol/Gag-Pol interactions is a novel target for small molecule inhibitors of HIV-1 production. Furthermore, these drugs can serve as useful probes to further understand processes involved in HIV-1 particle assembly and maturation.

Alkynes↗
PubMed2000

Long-term exposure of HIV type 1-infected cell cultures to combinations of the novel quinoxaline GW420867X with lamivudine, abacavir, and a variety of nonnucleoside reverse transcriptase inhibitors.

The novel quinoxaline GW420867X has been combined with a variety of nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1(IIIB)-infected CEM cell cultures. Whereas the antiviral efficacy of combinations of GW420867X with the NRTIs lamivudine (3TC) and abacavir (ABC) proved additive when administered to HIV-1-infected cells in a short-term (4-day) infection experiment, combination of GW420867X with the NRTIs 3TC and ABC resulted in a marked delay of virus breakthrough compared with the single drugs alone in a long-term (2-month) infection experiment. Delay of virus breakthrough was less pronounced for combinations of GW420867X with the NNRTIs. Combination of GW420867X with the NRTIs and NNRTIs resulted in additive inhibitory effects on recombinant HIV-1 reverse transcriptase as evident from isobolograms. Lamivudine plus GW420867X selected for the 3TC-specific M184I mutation and a number of NNRTI-characteristic mutations (i.e., V106A, V108I, and Y188H). Abacavir plus GW420867X selected only for NNRTI-specific mutations (i.e., K101E, K103R, V106A, and Y181C), including the novel L100V mutation. Combination of GW420867X with five different NNRTIs selected solely for NNRTI-specific mutations, and also for the L100V mutation in the combined presence of efavirenz, nevirapine, or emivirine, respectively. Five single-, two double-, and two triple-mutated HIV-1 strains that emerged from this study were evaluated for their sensitivity/resistance to AZT, lamivudine, and seven different NNRTIs. In all cases, efavirenz, GW420867X, and UC-781 retained pronounced antiviral potency. Our data suggest that combinations of GW420867X with 3TC, ABC, and NNRTIs (e.g., efavirenz) would be worth pursuing as therapeutic modalities against HIV-1 infections.

Alkynes↗
PubMed2006

Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors.

Many drug interactions with drugs used for the therapy of human immunodeficiency virus (HIV) occur at the level of different cytochrome P450 isozymes. Increasing evidence suggests that antiretrovirals may also modify activity and expression of active drug transport systems. Such interactions may alter drug absorption, elimination, and also drug distribution and reach clinical importance if thereby access to the target site is affected. Beyond P-glycoprotein, the family of multidrug resistance-related proteins (MRP/ABCC) substantially contributes to the elimination of numerous drugs and their metabolites. Because the interaction of MRPs with non-HIV protease inhibitor antiretrovirals has not been studied thoroughly, we investigated whether important non-nucleoside reverse transcriptase inhibitors (NNRTI) (delavirdine, efavirenz, and nevirapine), nucleoside reverse transcriptase inhibitors (NRTI) (abacavir, emtricitabine, and lamivudine), and tenofovir as a nonnucleotide reverse transcriptase inhibitor can interact with MRP1, MRP2, and MRP3 in vitro. Inhibition of these ABC transporters was quantified by confocal laser-scanning microscopy using the 5-chloromethylfluorescein diacetate assay. With the exception of abacavir, which had no effect on MRP3, all the test compounds increased intracellular 5-chloromethylfluorescein fluorescence in a concentration-dependent manner, and this effect was observed in all the overexpressing cell lines but not in the parental cell line, indicating inhibition of MRP1, MRP2, and MRP3. In conclusion, the present study provides the first evidence for a significant and concentration-dependent inhibition of MRPs by NNRTI, NRTI, and tenofovir, which was most pronounced for delavirdine, efavirenz, and emtricitabine, suggesting that this might contribute to some of the known drug interactions impairing HIV therapy and also to the superior effectiveness of combination pharmacotherapy.

Animals↗
PubMed2002

Body habitus changes and metabolic alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors.

BACKGROUND: Cross-sectional and retrospective surveys suggest that nucleoside reverse transcriptase inhibitors (NRTIs) contribute to the metabolic and morphologic alterations observed in patients on antiretroviral therapy (ART). OBJECTIVES: To assess the risk of developing body habitus changes (BHCs) and metabolic abnormalities in protease inhibitor (PI)-naive HIV-1-infected patients treated with two NRTIs, and the risk associated with each of these drugs. DESIGN: Prospective cohort study. PATIENTS AND METHODS: The BHCs occurring in 335 patients treated with two NRTIs were evaluated every 3 months. The laboratory tests included determination of CD4 cell counts and the measurement of HIV RNA, serum glucose, cholesterol, and triglyceride levels. Cox proportional hazard models were used to describe the factors associated with the development of BHCs. RESULTS: During a median exposure of 747.5 days, 46 patients (13.7%) developed BHCs: nine fat accumulation alone, 12 fat loss alone, and 25 combined fat loss and accumulation in different body regions. Fat loss alone occurred after a significantly longer median duration of treatment than the other two forms (p =.004). The risk of developing any BHC was significantly higher in female patients (p <.0001). Fat loss was the prevalent alteration in males. Hypertriglyceridemia was observed in 76 patients (22.7%), hypercholesterolemia in 35 (10.5%), and hyperglycemia in 48 (14.3%). The adjusted risk of developing hypertriglyceridemia was higher in the stavudine-treated patients (p =.04) and in those who had previously received ART (p =.02). The only independent factor associated with the development of hypercholesterolemia was to be ART experienced at baseline (p =.02), whereas age was associated with the development of hyperglycemia (p =.0096). CONCLUSIONS: Treatment with NRTIs may be responsible for the same morphologic alterations as those observed in patients treated with PIs. Moreover, altered triglyceride levels are also frequently observed. The different timing of presentation and gender distribution of BHCs suggest that multiple pathogenetic mechanisms are involved.

Adult↗
PubMed1999

Quantitative determination of abacavir (1592U89), a novel nucleoside reverse transcriptase inhibitor, in human plasma using isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection.

Abacavir is a novel nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection. A simple and rapid high-performance liquid chromatographic method for the quantification of abacavir in human plasma suitable for pharmacokinetic research purposes is described. Sample pretreatment consists of protein precipitation with perchloric acid. The supernatant is injected directly into the chromatographic system after centrifugation. The drug is separated from endogenous compounds by isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection at 285 nm. The method has been validated over the range of 20-2000 ng/ml using a volume of 300 microl of plasma. The assay is linear over this concentration range as indicated by the F-test for lack-of-fit. Within- and between-day precisions are less than 7.5% for all quality control samples. The lower limit of quantitation is 20 ng/ml and the recovery of abacavir is 88.1% (+/-1.3%). Frequently coadministered drugs did not interfere with the described methodology. Abacavir is stable in human plasma under various relevant storage conditions, for example when stored for 51 days at -20 degrees C. This validated assay is suited for use in pharmacokinetic studies with abacavir in human plasma and can readily be implemented in the setting of a hospital laboratory for the monitoring of abacavir concentrations.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Genotypic resistance to zidovudine as a predictor of failure of subsequent therapy with human immunodeficiency virus type-1 nucleoside reverse-transcriptase inhibitors.

To define factors predictive of failure to respond to nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type-1 (HIV-1)-infected subjects pretreated with zidovudine (ZDV), three groups of subjects shifted to double therapy with ZDV plus didanosine (ddI, n = 13), zalcitabine (ddC, n = 14), or lamivudine (3TC, n = 12) were retrospectively evaluated, with respect to addition of the second NRTI, at week 0 and week 24. Factors considered included duration of ZDV pretreatment, CD4+ cell counts, plasma HIV-1 RNA load, peripheral blood mononuclear cell HIV-1 DNA load, and HIV-1 DNA genotypic resistance to nucleoside reverse-transcriptase inhibitors. The three groups were well matched for baseline characteristics and did not differ significantly in virological and immunological response to the different combination treatments. Drug-specific resistance mutations were selected in more than half the cases by 3TC, but not by ddI and ddC. Low-level and substantial genotypic resistance to ZDV was detected 13 (33.3%) and in 19 (48.7%) patients at baseline, respectively, and evolved through week 24 in several patients. When subjects were divided into responders and nonresponders to the second nucleoside reverse-transcriptase inhibitor on the basis of a decrease of more than 0.5 log10 (n = 15) or less than 0.5 log10 (n = 21) in HIV-1 RNA, respectively, baseline genotypic ZDV resistance was the only independent predictor of failure in a logistic regression model (P = 0.003 or P = 0.024, depending on whether low-level resistance was considered or not, respectively). Thus, selection of ZDV resistance mutations may impair subsequent use of different nucleoside reverse-transcriptase inhibitor compounds.

Anti-HIV Agents↗
PubMed1999

Rapid quantification of delavirdine, a novel non-nucleoside reverse transcriptase inhibitor, in human plasma using isocratic reversed-phase high-performance liquid chromatography with fluorescence detection.

Delavirdine is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1-infected patients. A simple and rapid high-performance liquid chromatographic method for the quantification of delavirdine in human plasma suitable for drug monitoring in patients is described. Sample pretreatment consists of protein precipitation with acetonitrile and subsequent evaporation of the extract to concentrate the analyte. The drug is separated from endogenous compounds by isocratic reversed-phase, high-performance liquid chromatography coupled with fluorescence detection. The optimal excitation and emission wavelengths are 300 and 425 nm, respectively. The method has been validated over the range of 50-50 000 ng/ml using only 200 microl of plasma samples. The assay is linear over this concentration range as indicated by the F-test for lack of fit. Within- and between-day precisions are less than 4.4% for all quality control samples. The lower limit of quanititation is 50 ng/ml. Recovery of delavirdine from human plasma is 93.8%. Delavirdine is stable under various conditions, for example 1 h at 60 degrees C and one week at 4 degrees C. This validated assay is suited for use in pharmacokinetic studies with delavirdine and can readily be implemented in the setting of a hospital laboratory for the monitoring of delavirdine concentrations.

Anti-HIV Agents↗
PubMed1999

Quantitative determination of efavirenz (DMP 266), a novel non-nucleoside reverse transcriptase inhibitor, in human plasma using isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection.

Efavirenz is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1-infected individuals. A simple and rapid high-performance liquid chromatographic method for the quantification of efavirenz in human plasma suitable for therapeutic drug monitoring in plasma is described. Sample pretreatment consists of protein precipitation with acetonitrile and subsequent evaporation of the extract to concentrate the analyte. The drug is separated from endogenous compounds by isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection at 246 nm. The method has been validated over the range of 10 to 10,000 ng/ml using a volume of 250 microl of plasma. The assay is linear over this concentration range as indicated by the F-test for lack of fit. Within- and between-day precisions are less than 4.3% for all quality control samples. The lower limit of quantitation is 10 ng/ml and the recovery of efavirenz from human plasma is 106.4% (+/- 1.8%). Frequently co-administered drugs did not interfere with the described methodology. Efavirenz is stable under various relevant storage conditions, for example when stored for 24 h at room temperature. This validated assay is suited for use in pharmacokinetic studies with efavirenz and can readily be implemented in the setting of a hospital laboratory for the monitoring of efavirenz concentrations.

Acetonitriles↗
PubMedDate not supplied

Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than thirty structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and/or clinical development [tivirapine (TIBO R-86183), loviride (alpha-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio(pyridyl)imidazole derivative S-1153]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, preferably in combination with other anti-HIV agents, are used from the start at sufficiently high concentrations. In vitro, this procedure has been shown to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations containing NNRTIs, NRTIs and/or PIs may result in an effective viral suppression and ensuing immune recovery. However, this so-called HAART (highly active antiretroviral therapy) may also fail, and this necessitates the design of new and more effective drugs and drug cocktails.

HIV Infections↗
PubMed1998

The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than 30 structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are in preclinical or clinical development [thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097 and DMP 266 (efavirenz)]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, alone or in combination, are used from the start at sufficiently high concentrations. In vitro, this procedure has proved to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations of NNRTIs (nevirapine, delavirdine or efavirenz) with NRTIs (AZT, 3TC, ddI or d4T) and/or PIs (indinavir or nelfinavir) have been shown to afford a durable anti-HIV activity, as reflected by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-lymphocyte counts.

Alkynes↗
PubMed2002

Quantitative structure-activity relationship study of 2-arylsulfonyl-6-substituted benzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.

The reverse transcriptase inhibition of HIV-1, the most common form of HIV, by non-nucleoside 2-arylsulfonyl-6-substituted benzonitriles is analysed through Fujita-Ban and Hansch approaches. The analyses have helped to ascertain the role of different substituents in explaining the observed inhibitory actions of these compounds. From both approaches it appeared that SO2 instead of SO or S at X; and NH2 instead of F at Y (see Figure 1) are advantageous to improving the activity of a compound against HIV-1. This in turn leads to the suggestion that the 2-arylsulfonyl-6-aminobenzonitrile scaffold is the only appropriate structural entity that may further result into potential compounds. Further, the compounds having a OMe substituent at the orthoposition, the bulkier substituents at meta-positions and "no" substituent at para-position of 2-arylsulfonyl moiety are beneficial in raising the activity. The two quantitative structure-activity relationship (QSAR) analyses, differing in parametric approach, therefore, provided the grounds for rationalizing the substituent selection in designing more potent compounds of the series.

Anti-HIV Agents↗