Biological evaluation of molecules of the azaBINOL class as antiviral agents: Inhibition of HIV-1 RNase H activity by 7-isopropoxy-8-(naphth-1-yl)quinoline

AbstractInspired by bioactive biaryl-containing natural products found in plants and the marine environment, a series of synthetic compounds belonging to the azaBINOL chiral ligand family was evaluated for antiviral activity against HIV-1. Testing of 39 unique azaBINOLs in a singleround infectivity assay resulted in the identification of three promising antiviral compounds, including 7-isopropoxy-8-(naphth-1-yl)quinoline (azaBINOLB#24), which exhibited low-micromolar activity. The active compounds and several close structural analogues were further tested against three different HIV-1 envelope pseudotyped viruses as well as in a full-virus replication system (EASY-HIT). Mode-of-action studies using a time-of-addition assay indicated that azaBINOLB#24acts after viral entry but before viral assembly and budding. HIV-1 reverse transcriptase (RT) assays that individually test for polymerase and RNase H activity were used to demonstrate thatB#24inhibits RNase H activity, most likely allosterically. Further binding analysis using bio-layer interferometry (BLI) showed thatB#24interacts with HIV-1 RT in a highly specific manner. These results indicate that azaBINOLB#24is a potentially viable, novel lead for the development of new HIV-1 RNase H inhibitors. Furthermore, this study demonstrates that the survey of libraries of synthetic compounds, designed purely with the goal of facilitating chemical synthesis in mind, may yield unexpected and selective drug leads for the development of new antiviral agents.

Download Full-text

Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: Synthesis and Biological Evaluation of Novel Quinoxalinylethylpyridylthioureas as Potent Antiviral Agents

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632020001100206 ◽

2000 ◽

Vol 11 (2) ◽

pp. 141-155 ◽

Cited By ~ 1

Author(s):

G Campiani ◽

M Fabbrini ◽

E Morelli ◽

V Nacci ◽

G Greco ◽

...

Keyword(s):

Reverse Transcriptase ◽

Antiviral Agents ◽

Human Monocyte ◽

Biological Evaluation ◽

Single Amino Acid ◽

Enzymatic Assays ◽

Immunodeficiency Virus ◽

Heterocyclic Derivatives ◽

Rt Inhibitors ◽

Hiv 1

New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L100I, K103N, V106A, Y181I and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.

Download Full-text

Diversity-oriented solid-phase synthesis and biological evaluation of oligonucleotide hairpins as HIV-1 RT RNase H inhibitors

Nucleic Acids Research ◽

10.1093/nar/gkh948 ◽

2004 ◽

Vol 32 (21) ◽

pp. 6164-6175 ◽

Cited By ~ 7

Author(s):

Rami N. Hannoush ◽

Kyung-Lyum Min ◽

Masad J. Damha

Keyword(s):

Solid Phase Synthesis ◽

Solid Phase ◽

Biological Evaluation ◽

Rnase H ◽

Phase Synthesis ◽

Synthesis And Biological Evaluation ◽

Hiv 1

Download Full-text

Chemical Characterization and Anti-HIV-1 Activity Assessment of Iridoids and Flavonols from Scrophularia trifoliata

Molecules ◽

10.3390/molecules26164777 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4777

Author(s):

Francesca Guzzo ◽

Rosita Russo ◽

Cinzia Sanna ◽

Odeta Celaj ◽

Alessia Caredda ◽

...

Keyword(s):

Antiviral Activity ◽

Wide Spectrum ◽

Iridoid Glycosides ◽

Antiviral Agents ◽

Chemical Characterization ◽

Biological Properties ◽

Rnase H ◽

Chemical Structures ◽

First Time ◽

Hiv 1

Plants are the everlasting source of a wide spectrum of specialized metabolites, characterized by wide variability in term of chemical structures and different biological properties such antiviral activity. In the search for novel antiviral agents against Human Immunodeficiency Virus type 1 (HIV-1) from plants, the phytochemical investigation of Scrophularia trifoliata L. led us to isolate and characterize four flavonols glycosides along with nine iridoid glycosides, two of them, 5 and 13, described for the first time. In the present study, we investigated, for the first time, the contents of a methanol extract of S. trifoliata leaves, in order to explore the potential antiviral activity against HIV-1. The antiviral activity was evaluated in biochemical assays for the inhibition of HIV-1Reverse Transcriptase (RT)-associated Ribonuclease H (RNase H) activity and HIV-1 Integrase (IN). Three isolated flavonoids, rutin, kaempferol-7-O-rhamnosyl-3-O-glucopyranoside, and kaempferol-3-O-glucopyranoside, 8–10, inhibited specifically the HIV-1 IN activity at submicromolar concentration, with the latter being the most potent, showing an IC50 value of 24 nM.

Download Full-text

Design, synthesis and biological evaluation of 3-hydroxyquinazoline-2,4(1H,3H)-diones as dual inhibitors of HIV-1 reverse transcriptase-associated RNase H and integrase

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2019.07.011 ◽

2019 ◽

Vol 27 (17) ◽

pp. 3836-3845 ◽

Cited By ~ 2

Author(s):

Ping Gao ◽

Xiqiang Cheng ◽

Lin Sun ◽

Shu Song ◽

Mar Álvarez ◽

...

Keyword(s):

Reverse Transcriptase ◽

Biological Evaluation ◽

Rnase H ◽

Design Synthesis ◽

Dual Inhibitors ◽

Synthesis And Biological Evaluation ◽

Hiv 1

Download Full-text

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190717163959 ◽

2019 ◽

Vol 19 (18) ◽

pp. 1650-1675 ◽

Cited By ~ 2

Author(s):

Damoder Reddy Motati ◽

Dilipkumar Uredi ◽

E. Blake Watkins

Keyword(s):

Small Molecule ◽

Viral Entry ◽

Biological Evaluation ◽

New Drugs ◽

Design Synthesis ◽

Mortality And Morbidity ◽

Glycoprotein Gp120 ◽

Hiv Entry ◽

Immunodeficiency Syndrome ◽

Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

Download Full-text