Anti-human Immunodeficiency Virus Agent Research Articles

Synthesis and anti-HIV activity of non-nucleoside reverse-transcriptase inhibitor DB02 phosphate derivatives based on water-soluble optimization.

To improve the water solubility of anti-human immunodeficiency virus(HIV) agent DB02, an excellent non-nucleoside reverse-transcriptase inhibitor(NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P-2, which possessed a superior potency to the lead compound DB02 against wild-type HIV-1 and a variety of HIV-resistant mutant viruses significantly. Furthermore, the water solubility of P-2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P-2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C-2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S-DACOs type of NNRTIs.

Advances in Nucleoside and Nucleotide Analogues in Tackling Human Immunodeficiency Virus and Hepatitis Virus Infections.

Nucleoside and nucleotide analogues are structurally similar antimetabolites and are promising small-molecule chemotherapeutic agents against various infectious DNA and RNA viruses. To date, these analogues have not been documented in-depth as anti-human immunodeficiency virus (HIV) and anti-hepatitis virus agents, these are at various stages of testing ranging from pre-clinical, to those withdrawn from trials, or those that are approved as drugs. Hence, in this review, the importance of these analogues in tackling HIV and hepatitis virus infections is discussed with a focus on the viral genome and the mechanism of action of these analogues, both in a mutually exclusive manner and their role in HIV/hepatitis coinfection. This review encompasses nucleoside and nucleotide analogues from 1987 onwards, starting with the first nucleoside analogue, zidovudine, and going on to those in current clinical trials and even the drugs that have been withdrawn. This review also sheds light on the prospects of these nucleoside analogues in clinical trials as a treatment option for the COVID-19 pandemic.

Pharmacophore model and atom-based 3D quantitative structure activity relationship (QSAR) of human immunodeficiency virus-1 (HIV-1) capsid assembly inhibitors

A potential anti-Human Immunodeficiency Virus (HIV) agent with novel mode of action is urgently needed to fight against drug resistance HIV. The HIV capsid protein is important for both late and early stages of the viral replication cycle and emerged as a promising target for the developing of small molecule inhibitors of HIV. We design a Pharmacophore and 3D Quantitative structure activity relationship (QSAR) model for HIV Capsid Protein inhibitors, which helps to identify overall aspects of molecular structure that govern activity and for the prediction of novel HIV Capsid inhibitors. The hypothesis was developed with a survival score of 3.6.The features, that is, two aromatic rings, one hydrophobic site and two acceptor regions were present in all the active compounds with good fitness score. Pharmacophore model was then validated by a partial least square and regression-based PHASE 3D QSAR cross-validation. The leave-n-out cross validation for test set (Q2) of the hypothesis is 0.636, the standard deviation (SD) value is 0.338, and the variance ratio (F-test) value is 74.5. Hypothesis also showed a leave-n-out cross validation for training set (R2, 0.928). Interestingly, the predicted activity of true test set compounds was found in the close vicinity of their experimental activity suggesting the methodology used and models generated can be applied to identify potential new chemical entities with better HIV-1 capsid assembly inhibition.Communicated by Ramaswamy H. Sarma

Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?

Although several viruses can easily infect the central nervous system (CNS), antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs). These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1), multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5), and breast cancer resistance protein (ABCG2 or BCRP). Inhibitors of AETs may be considered, but their co-administration causes serious unwanted effects. Nasal administration of antiviral drugs is therefore proposed in order to overcome the aforementioned problems, but innovative devices, formulations (thermoreversible gels, polymeric micro- and nano-particles, solid lipid microparticles, nanoemulsions), absorption enhancers (chitosan, papaverine), and mucoadhesive agents (chitosan, polyvinilpyrrolidone) are required in order to selectively target the antiviral drugs and, possibly, the AET inhibitors in the CNS. Moreover, several prodrugs of antiretroviral agents can inhibit or elude the AET systems, appearing as interesting substrates for innovative nasal formulations able to target anti-Human Immunodeficiency Virus (HIV) agents into macrophages of the CNS, which are one of the most important HIV Sanctuaries of the body.

Expanding the Antiviral Spectrum of 3-Fluoro-2-(phosphonomethoxy)propyl Acyclic Nucleoside Phosphonates: Diamyl Aspartate Amidate Prodrugs.

Acyclic nucleosides containing a 3-fluoro-2-(phosphonomethoxy)propyl (FPMP) side chain are known to be moderately potent antihuman immunodeficiency virus (HIV) agents, while being completely devoid of antiviral activity against a wide range of DNA viruses. The derivatization of the phosphonic acid functionality of FPMPs with a diamyl aspartate phenoxyamidate group led to a novel generation of compounds that not only demonstrate drastically improved antiretroviral potency but also are characterized by an expanded spectrum of activity that also covers hepatitis B and herpes viruses. The best compound, the (S)-FPMPA amidate prodrug, exerts anti-HIV-1 activity in TZM-bl and peripheral blood mononuclear cells at low nanomolar concentrations and displays excellent potency against hepatitis B virus (HBV) and varicella-zoster virus (VZV). This prodrug is stable in acid and human plasma media, but it is efficiently processed in human liver microsomes with a half-life of 2 min. The (R) isomeric guanine derivative emerged as a selectively active anti-HIV and anti-HBV inhibitor, while being nontoxic to human hepatoblastoma cells. Notably, the pyrimidine containing prodrug (S)-Asp-FPMPC is the only congener within this series to demonstrate micromolar antihuman cytomegalovirus (HCMV) potency.

Synthesis and therapeutic potential of quinoline derivatives

Quinolines are nitrogen-containing bicyclic compounds that are widely found throughout Nature in various forms. Quinoline derivatives are utilized in the areas of medicine, food, catalysts, dyes, materials, refineries, electronics, etc. The quinoline nucleus is present in numerous biological compounds, e.g., antimalarial, antimicrobial, antimycobacterial, antidepressant, anticonvulsant, antiviral, anticancer, antihypertensive, platelet-derived growth factor (PDGF) receptor tyrosine kinase (RTK) inhibitory, antiinflammatory, antioxidant, and anti-human immunodeficiency virus (HIV) agents. However, owing to the swift development of new molecules containing this nucleus, many research reports have been generated in a brief span of time. There therefore seems to be a requirement to collect recent information in order to understand the current status of the quinoline nucleus in medicinal chemistry research, focusing in particular on the numerous attempts to synthesize and investigate new structural prototypes with more effective antimalarial, antimicrobial, and anticancer activity.

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats.

The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96µg/hmL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13%. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

Oral and Vaginal Tenofovir for Genital Herpes Simplex Virus Type 2 Shedding in Immunocompetent Women: A Double-Blind, Randomized, Cross-over Trial.

Tenofovir is a potent anti-human immunodeficiency virus (HIV) agent that decreased risk of herpes simplex virus type 2 (HSV-2) acquisition in HIV pre-exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat end point was within-person comparison of genital HSV shedding and lesion rates. 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by -0.50 (-0.86-0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (relative risk [RR] = 0.74, P = .006) and lesion rates (RR = 0.75, P = .032); quantity of virus shed decreased by 0.41 log10 copies/mL. Oral TDF modestly decreased HSV shedding and lesion rate, and quantity of virus shed when used consistently. Vaginal TFV gel decreased quantity of virus shed by 60%. In contrast to effects on HSV-2 acquisition, tenofovir is unlikely to provide clinically meaningful reductions in the frequency of HSV shedding or genital lesions. NCT01448616.

Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists’ arsenal

Experimental data indicate that several pharmacological agents that have long been used for the management of various diseases unrelated to cancer exhibit profound in vitro and in vivo anticancer activity. This is of major clinical importance, since it would possibly aid in reassessing the therapeutic use of currently used agents for which clinicians already have experience. Further, this would obviate the time-consuming process required for the development and the approval of novel antineoplastic drugs. Herein, both pre-clinical and clinical data concerning the antineoplastic function of distinct commercially available pharmacological agents that are not currently used in the field of oncology, ie, nonsteroidal anti-inflammatory drugs, antihypertensive agents, and anti-human immunodeficiency virus agents inhibiting viral protease, are reviewed. The aim is to provide integrated information regarding not only the molecular basis of the antitumor function of these agents but also the applicability of the reevaluation of their therapeutic range in the clinical setting.

Petiveria alliacea L (Guinea Hen Weed) and Its Major Metabolite Dibenzyl Trisulfide Demonstrate HIV-1 Reverse Transcriptase Inhibitory Activity

Aim: The human immunodeficiency virus (HIV) remains a major public health concern despite the discovery and development of Highly Active Antiretroviral Therapies (HAART). There is as such a need to continue to search for new and effective therapies for this global pandemic. In an effort to discover new anti HIV agents, the aim of this study was to determine the anti HIV-1 activity of Petiveria alliacea and its metabolites . Methodology: The extracts of P. alliacea and dibenzyl trisulfide were screened for anti HIV-1 properties in primary peripheral blood mononuclear cells (PBMCs) infected with the HIV-1JR-CSF strain.

Molecular structure, vibrational spectra, UV–vis, NBO, and NMR analyses on nevirapine using ab initio DFT methods

Nevirapine is an anti-human immunodeficiency virus (HIV) agent that belongs to the class of the non-nucleoside inhibitors of the HIV-1 virus reverse transcriptase. Spectral characteristics of nevirapine have been probed into by methods of Fourier transform infrared (FTIR), FT-Raman, UV-visible, and quantum chemistry. The UV spectrum was measured in methanol. In order to gain some valuable insight into the recorded spectrum, the quantum mechanical calculations were performed for nevirapine using both ZINDO and time-dependent density functional theory at B3LYP/6-31G(d,p) level. The optimized molecular geometry, bond orders, natural bond order analysis, and harmonic vibrational wavenumbers of nevirapine were calculated by restricted Hartree-Fock and density functional B3LYP methods with the 6-31G(d,p) basis set using Gaussian 03 W program. The harmonic vibrational frequencies calculated have been compared with experimental FTIR and FT-Raman spectra. The restricted Hartree-Fock and density functional theory-based nuclear magnetic resonance (NMR) calculation procedure was also performed, and it was used for assigning the 13C and 1H NMR chemical shifts of nevirapine.

Synthesis of Novel 3′-Hydroxymethyl 5′-Deoxythreosyl Phosphonic Acid Nucleoside Analogues as Potent Antiviral Agents

A very efficient synthetic route to novel 3′-hydroxymethyl 5′-deoxythreosyl phosphonic acid nucleosides was described. The discovery of threosyl phosphonate nucleoside (PMDTA, EC50 = 2.53 μM) as a potent antihuman immunodeficiency virus (anti-HIV) agent has led to the synthesis and biological evaluation of 3′-modified 5′-deoxy versions of the threosyl phosphonate nucleosides. 3′-Hydroxymethyl 5 ′-deoxythreosyl phosphonic acid nucleoside analogues 15, 19, 24, and 28 were synthesized from 1,3-dihydroxyacetone and tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 19 exhibits moderate in vitro anti-HIV-1 activity (EC50 = 10.2 μM).

Synthesis and Evaluation of Novel 4‐Substituted Styryl Quinazolines as Potential Antimicrobial Agents

In an attempt to afford possible antibacterial and anti-human immunodeficiency virus (HIV) agents, a series of 22 novel styryl quinazoline-based heterocyclic entities were designed and synthesized. Various substituted aryl urea and thiourea cores were incorporated at position 4 of quinazoline, followed by styrylation of position 2, aiming at an augmented biological potential. The synthesized compounds were well characterized through IR, (1) H NMR, (13) C NMR and elemental analyses. All compounds were screened for their in vitro anti-HIV activity against the HIV-1 (IIIB) and HIV-2 (ROD) strains. The antibacterial activity was also evaluated against various pathogenic Gram-positive and Gram-negative bacterial strains.

ChemInform Abstract: Nucleotide Dimers as Anti Human Immunodeficiency Virus Agents

ChemInform Abstract: Nucleotide Dimers as Anti Human Immunodeficiency Virus Agents

Anti-AIDS Agents. 78. Design, Synthesis, Metabolic Stability Assessment, and Antiviral Evaluation of Novel Betulinic Acid Derivatives as Potent Anti-Human Immunodeficiency Virus (HIV) Agents

In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC(50) = 0.09 microM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N'-[N-[3beta-hydroxy-lup-20(29)-en-28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3beta-O-(3',3'-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC(50) values of 0.007 and 0.006 microM, respectively. These results are slightly better than that of bevirimat (2, 3',3'-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.

Prediction of anti-HIV activity of imidoyl thioureas: QSAR approach

AbstractIn pursuit of better anti-human immunodeficiency virus (HIV) agents, quantitative structure-activity relationship (QSAR) studies were performed on a series of imidoyl thiourea (ITU) derivatives using WIN CAChe 6.1. Stepwise multiple linear regression analysis was performed to derive QSAR models, which were further evaluated for statistical significance and predictive power by internal and external validation. The best QSAR model was selected, having correlation coefficient (R) of 0.844 and cross-validated squared correlation coefficient (Q 2 ) of 0.617. The QSAR model reported herein providing interest insight in understanding the hydrophobic, electronic, and structural requirements of anti-HIV activity among the ITU derivatives. The results of the present study may be useful on the designing of more potent ITU analogs as anti-HIV agents.Graphical AbstractThe presence of -CH2- group at A is must for better anti-HIV activity.[IMAGE]

Optimization of Azoles as Anti-Human Immunodeficiency Virus Agents Guided by Free-Energy Calculations

Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole core has been guided by free energy perturbation (FEP) calculations to provide potent non-nucleoside inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (NNRTIs). An FEP "chlorine scan" was performed to identify the most promising sites for substitution of aryl hydrogens. This yielded NNRTIs 8 and 10 with activities (EC50) of 820 and 310 nM for protection of human T-cells from infection by wild-type HIV-1. FEP calculations for additional substituent modifications and change of the core heterocycle readily led to oxazoles 28 and 29, which were confirmed as highly potent anti-HIV agents with activities in the 10-20 nM range. The designed compounds were also monitored for possession of desirable pharmacological properties by use of additional computational tools. Overall, the trends predicted by the FEP calculations were well borne out by the assay results. FEP-guided lead optimization is confirmed as a valuable tool for molecular design including drug discovery; chlorine scans are particularly attractive since they are both straightforward to perform and highly informative.

QSAR model of triterpene derivatives as potent anti-HIV agents

Triterpenes derivatives are a promising class of anti-human immunodeficiency virus (anti-HIV) agents. A series of triterpene derivatives have been studied for quantitative structure–activity relationship with multiple linear regression (MLR) and artificial neural networks (ANN). The linear model with MLR performed poorly while the nonlinear model with ANN preformed well. For the ANN model with architecture of 5-6-1, the root mean square error for the training set, validation set and the prediction set are 0.2019, 0.2214 and 0.2883, respectively, and the r for the training set, validation set and the prediction set are 0.8895, 0.8843 and 0.8819, respectively. In this study, different methods were used to select the most relevant descriptors for MLR and ANN. Finally, five descriptors, EB, LOGP, HOMO, HE and ω, were selected for both MLR and ANN. The result indicates these descriptors are playing an important role on the anti-HIV activity of triterpene derivatives.

Intracellular Metabolism of the Nucleotide Prodrug GS-9131, a Potent Anti-Human Immunodeficiency Virus Agent

GS-9131 is a phosphonoamidate prodrug of the novel ribose-modified phosphonate nucleotide analog GS-9148 that demonstrates potent anti-human immunodeficiency virus type 1 (HIV-1) activity and an excellent resistance profile in vitro. Prodrug moieties were optimized for the efficient delivery of GS-9148 and its active diphosphate (DP) metabolite to lymphoid cells following oral administration. To understand the intracellular pharmacology of GS-9131, incubations were performed with various types of lymphoid cells in vitro. The intracellular accumulation and antiviral activity levels of GS-9148 were limited by its lack of cellular permeation, and GS-9131 increased the delivery of GS-9148-DP by 76- to 290-fold relative to that of GS-9148. GS-9131 activation was saturable at high extracellular concentrations, potentially due to a high-affinity promoiety cleavage step. Once inside the cells, GS-9148 was efficiently phosphorylated, forming similar amounts of anabolites in primary lymphoid cells. The levels of GS-9148-DP formed in peripheral blood mononuclear cells infected with HIV-1 were similar to that in uninfected PBMCs, and approximately equivalent intracellular concentrations of GS-9148-DP and tenofovir (TVF)-DP were required to inhibit viral replication by 90%. Once it was formed, GS-9148-DP was efficiently retained in activated CD4(+) cells, with a half-life of 19 h. In addition, GS-9131 showed a low potential for drug interactions with other adenine nucleoside/nucleotide reverse transcriptase inhibitors, based on the lack of competition for anabolism between suprapharmacologic concentrations of GS-9148 and TVF and the lack of activity of GS-9131 metabolites against purine nucleoside phosphorylase, an enzyme involved in the clearance of 2',3'-dideoxyinosine. Together, these observations elucidate the cellular pharmacology of GS-9131 and illustrate its efficient loading of lymphoid cells, resulting in a prolonged intracellular exposure to the active metabolite GS-9148-DP.

Pharmacokinetics of the anti-human immunodeficiency virus agent 1-(beta-D-dioxolane)thymine in rhesus monkeys.

Beta-D-dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h(-1); fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.