Pyrazole Containing Anti-HIV Agents: An Update

Background: Pyrazole scaffolds have gained importance in drug discovery and development for various pharmacological activities like antiviral, antifungal, anticancer, antidepressant, anti-inflammatory, antibacterial, etc. Additionally, the pyrazole moiety has shown potent anti-HIV activity as a core heterocycle or substituted heterocycles derivatives (mono, di, tri, tetra, and fused pyrazole derivatives). To assist the development of further potential anti-HIV agents containing pyrazole nucleus, here we have summarized pyrazole containing anti-HIV compounds that have been reported by researchers all over the world for the last two decades. Objective: The present review concentrates on an assortment of pyrazole containing compounds, particularly for potential therapeutic activity against HIV. Methods: Google Scholar, Pubmed, and SciFinder were searched databases with ‘‘pyrazol’’ keywords. Further, the year of publication and keywords ‘‘Anti-HIV’’ filter was applied to obtain relevant reported literature for anti-HIV agents containing pyrazole as a core or substituted derivatives. Results: This review article has shown the comprehensive compilation of 220 compounds containing pyrazole nucleus and possessing anti-HIV activity by sorting approximately 40 research articles from 2001 to date. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (13), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (31), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (88), 3-cyanophenoxypyrazole derivative (130), and 4-(4-chlorophenyl)-5-(4-methyl-5-((4-nitrophenyl)diazenyl)thiazol-2-yl)-3-phenyl-5,6-dihydro-4H-pyrazolo[4,3-d]isoxazole (178) were the most potent mono-, di-, tri-, tetra-substituted, and fused pyrazole derivatives, respectively, which have shown potent anti-HIV activity among all the described derivatives as compared with standard anti-HIV drugs. Conclusion: This review article provides an overview of the potential therapeutic activity of pyrazole derivatives against HIV that will be helpful for designing pyrazole containing compounds for anti-HIV activity.

Inflammation and Intracellular Exposure of Dolutegravir, Darunavir, Tenofovir and Emtricitabine in People living with HIV

Background: Antiretroviral therapy reduces systemic inflammation and immune activation, but not to levels like HIV-negative. Limited drug penetration within tissues has been argued as potential mechanism of persistent inflammation. Data on the role of inflammation on plasma/intracellular (IC) pharmacokinetics (PK) of ARV drugs through to downregulation/expression of cytochrome P450 3A/membrane transport proteins are limited. Aim of this study was to investigate the correlation between inflammation markers and plasma/IC PK of different ARVs regimen in HIV-positive patients. Methods: We included in the study ART-treated HIV+ pts switching to 3 different ARV regimens: 1) DTG-based dual-therapy plus boosted-PIs, 2) DTG-based triple-therapy without PIs, 3) DRV/c-based triple-therapy. Plasma and IC ARV drugs concentration means at the end of dosing interval (T0), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed. Results: 60 samples from pts included in the switching study were used for measuring plasma and IC concentrations of HIV drugs. No significative differences between CRP, sCD14, IL-6 and LPS values in 3 arms of therapy were observed. Significant correlation was observed between tenofovir plasma concentrations and sCD14 (p<0.001), DRV plasma concentration and sCD14 (p=0,07) and DRV IC/plasma ratio and Log10 IL-6 concentrations (p=0.04). Furthermore, in 24 pts on DTG-TT, we observed a negative trend between DTG IC concentrations and sCD14 (p=0.09). Conclusions: Our preliminary data support the hypothesis of lower IC concentrations of DRV and DTG in pts with higher plasma IM, suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.

The mystery of chemistry behind the mechanism of action of anti-HIV drugs: A docking approach at an atomic level

The effect of HIV-1 on a human’s immune system cannot be ignored. This is the virus that reduces the power of the immune system to fight against any disease. Of course, many anti-HIV drugs are available, and many computational studies have been done to find out their mechanism of action, but the computational study regarding the chemistry behind the mechanism of action was not done yet. Therefore, the main objective of the study was to clarify the chemistry behind the mechanism of action of commercially available anti-HIV drugs. The drugs taken in the presented study were Entry Inhibitors (EIs) and Non-nucleoside reverse transcriptase inhibitors. First, literature data was evaluated computationally to ensure the reliability of the software used for the presented study. It was found that interaction-based experimental results and computationally evaluated results of the literature data were the same. After that, by following the same procedure, a docking study was done on the drugs taken in the current study. In addition, the residues involved in the interactions of EIs and NNRTIs with their receptors were studied to determine the chemistry that acts behind the action of both. It was found that EIs and NNRTIs work differently. It was also predicted that the derivatization of both drugs could make them more effective and active. Therefore, the presented study will be very helpful in the field of medicinal science.

Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane-Sodium Iodide Promoted Vorbrüggen Glycosylation

By simply adding water and sodium iodide (NaI) to chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor for N-glycosylation of silylated cytosine derivatives, leading to cis ox-athiolane products with up to 95% yield and >20:1 dr. This telescoped sequence is followed by recrystallization and borohydride reduction, resulting in rapid synthesis of (±)-FTC/3TC from an achiral tartrate ester.

A Combination of Amino Acid Mutations Leads to Resistance to Multiple Nucleoside Analogs in Reverse Transcriptases from HIV-1 Subtypes B and C

Resistance to anti-Human Immunodeficiency Virus (HIV) drugs has been a problem from the beginning of antiviral drug treatments. The recent expansion of combination antiretroviral therapy worldwide has led to an increase in resistance to antiretrovirals; understanding the mechanisms of resistance is increasingly important. In this study, we analyzed reverse transcriptase (RT) variants based on sequences derived from an individual who had a low-level rebound viremia while undergoing therapy with abacavir, azidothymidine (AZT or Zidovudine), and (−)-L-2′,3′-dideoxy-3′-thiacytidine (Lamivudine or 3TC). The RT had mutations at positions 64, 67, 70, 184, 219, and a threonine insertion after amino acid 69 in RT. The virus remained partially susceptible to the nucleoside reverse transcriptase inhibitor (NRTI) regimen. We show how these mutations affect the ability of NRTIs to inhibit DNA synthesis by RT. The presence of the inserted threonine reduced the susceptibility of the RT mutant to inhibition by Tenofovir.

Biologically oriented synthesis of medicines (BIODS) based on heterylpoxid 2,5-disubstituted 1,3,4-oxadiazoles (Part 2)

Heterocyclic compounds make a very important branch of organic chemistry, and it has always been an interesting area of study in medical chemistry. They are present in a variety of drugs, vitamins and biologically active compounds. Over two decades, 1,3,4-oxadiazoles have been of interest to chemists owing to their diverse therapeutic potential; the studies focus mainly on the principles of combinatorial chemistry with a broad spectrum of biological activity. In the continuation of the review article, the general literature sources that consider chemical heteryl derivatives of 2,5-disubstituted 1,3,4-oxadiazoles as important synthetic substrates and precursors for biologically oriented synthesis, are systematized. Heterocyclic 1,3,4-oxadiazoles and their derivatives are widely used as antibacterial, fungicidal, anti-inflammatory, antidiabetic, anticancer, antitubercular, antioxidant, antimalarial, analgesic, anticonvulsant, antidepressant and anti-HIV drugs. It is important to note that the combination of 1,3,4-oxadiazole nuclei with different heterocyclic moieties in some cases had synergistic effect. The aim of the work is the search for new activities, systematization and generalization of literature sources on methods of biologically oriented drug synthesis (BIODS) based on heteryl derivatives of 2,5-disubstituted 1,3,4-oxadiazoles. Conclusions. The article analyzes, generalizes and systematizes the data obtained from the literature that describes the results of the study of the biological activity of 1,3,4-oxadiazoles, which allowed to confirm their diverse pharmacological and biological potential. It is established that oxadiazoscafold as the main structural component is found in various biologically active compounds which evidences the relevance of its further studies as a perspective structural matrix for construction of drug-like molecules. The analysis of the presented material demonstrates the significance and prospectivity of biologically oriented drugs of this segment of the chemistry of nitrogen-containing heterocycles.

Therapeutic potential of indole derivatives as anti-HIV agents: A mini-review

: Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), is one of the leading causes of human deaths. The advent of different anti-HIV drugs over different disease progress has made AIDS/HIV from a deadly infection to chronic and manageable disease. However, the development of multidrug-resistant viruses, together with the severe side effects of anti-HIV agents, compromised their efficacy and limited the treatment options. Indoles, the most common frameworks in the bioactive molecules, represent attractive scaffolds for the design and development of novel drugs. Indole derivatives are potential inhibitors of HIV enzymes such as reverse transcriptase, integrase and protease, and some indole-based agents like Delavirdine have already been applied in clinics or under clinical evaluations for the treatment of AIDS/HIV, revealing that indole moiety is a useful template for the development of anti-HIV agents. This review focuses on the recent advancement of indole derivatives including indole alkaloids, hybrids, and dimers with anti-HIV potential, covering articles published between 2010 and 2020. The chemical structures, structure-activity relationship and mechanisms of action are also discussed.