Bioinspired Pyrano[2,3-f]chromen-8-ones: Ring C-Opened Analogues of Calanolide A: Synthesis and Anti-HIV-1 Evaluation

Khalymbadzha, Igor A.; Fatykhov, Ramil F.; Butorin, Ilya I.; Sharapov, Ainur D.; Potapova, Anastasia P.; Muthipeedika, Nibin Joy; Zyryanov, Grigory V.; Melekhin, Vsevolod V.; Tokhtueva, Maria D.; Deev, Sergey L.; Kukhanova, Marina K.; Mochulskaya, Nataliya N.; Tsurkan, Mikhail V.

doi:10.3390/biomimetics9010044

Cited by 2 publications

(3 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Coumarins with anti-HIV-1 activity have been identified from Calophyllum inophylum and Calphylum lanigerrum plants. Calanolide A, also known as 11,12-dihydro-2H,6H,10H-dipyron[2,3-f2′,3′-h]chromen-2-one, was isolated from Calophyllum lanigerum and identified as the first anti-HIV-1 substance [ 23 , 24 ]. It has demonstrated a broad spectrum of anti-HIV-1 activity, including AZT and pyridinone drug-resistant strains [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has demonstrated a broad spectrum of anti-HIV-1 activity, including AZT and pyridinone drug-resistant strains [ 23 ]. Due to difficulties in isolating calanolide A from natural sources and its total synthesis, additional clinical trials have been halted, and its therapeutic index is low [ 24 ]. In light of this constraint, a recent work chemically synthesised calanolide A analogues by adding nitrogen heterocycles or aromatic groups into ring C [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…Due to difficulties in isolating calanolide A from natural sources and its total synthesis, additional clinical trials have been halted, and its therapeutic index is low [ 24 ]. In light of this constraint, a recent work chemically synthesised calanolide A analogues by adding nitrogen heterocycles or aromatic groups into ring C [ 24 ]. This synthesised calanolide A analogue demonstrated moderate anti-HIV-1 activity on reverse transcriptase.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Anti-HIV Activity and Immunomodulatory Properties of Fractionated Crude Extracts of Alternaria alternata

Kubheka,

Ndlovu,

Mkhwanazi

2024

Microorganisms

View full text Add to dashboard Cite

Developing new anti-human immunodeficiency virus (HIV) drug candidates that target different sites in HIV-1 replication, with better resistance profiles and lower drug toxicity, is essential to eradicating HIV. This study investigated the potential of fractionated crude extracts of Alternaria alternata as immunomodulatory or anti-HIV drug candidates. Solid-phase extraction (SPE) was used to fractionate A. alternata PO4PR2 using three different columns: MAX (Mixed-mode, strong Anion-eXchange), MCX (Mixed-mode, strong Cation-eXchange), and HLB (Hydrophilic–Lipophilic Balance) with methanol gradient methods (5%, 45%, and 95%). An MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to assess the cell viability and cytotoxicity of the fractionated crude extract A. alternata PO4PR2 in the TZM-bl cell lines. This was followed by a luciferase-based antiviral assay to assess the antiviral activity of A. alternata PO4PR2. A time of addition (TOA) assay was performed to ascertain the mechanism of inhibition employed by the fractionated crude extract of A. alternata PO4PR2 in the HIV life cycle. The p24 titer was determined using an ELISA, while a luciferase-based antiviral assay was used to evaluate the HIV percentage inhibition for different HIV-1 replication cycles. The TOA assay was established using antiviral drugs that target different sites in the HIV replication cycle. These included maraviroc, azidothymidine, raltegravir, and amprenavir. The immunomodulatory effect of the fractionated crude extracts on CD4+ T cells was measured by a flow cytometric analysis, for which fluorochrome-labelled monoclonal antibodies were used as markers for activation (CD38 and HLA-DR) and exhaustion (PD-1). The MCX fraction demonstrated a more significant anti-HIV inhibition than that of the fractions generated in other columns, with an IC50 of 0.3619 µg/mL, an HIV inhibition of 77%, 5% HLB (IC50: 0.7232 µg/mL; HIV inhibition of 64%), and 5% MAX (IC50: 5.240 µg/mL; HIV inhibition of 67%). It was evident from the time of addition data that the crude extract and the 5% MCX fraction inhibited viral binding (68%), reverse transcription (75%), integration (98%), and proteolysis (77%). It was shown that A. alternata (the MCX fraction) have a significant inhibitory effect on reverse transcription (75% HIV inhibition) and integration (100% HIV inhibition). The 5% MCX (p = 0.0062), 5% HLB (p = 0.0269), and 5% MAX (p = 0.0117) fractionated A. alternata crude extracts had low levels of CD4+ T cell (CD38 + HLA-DR+) activation compared to those of the AZT treatment, while CD4+ T cell activation was insignificant. The 5% MAX and HLB A. alternata fractions may possess immunomodulatory compounds with less anti-HIV-1 activity. A. alternata could be a key source of innovative anti-HIV drugs with immunomodulatory characteristics.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-HIV Activity and Immunomodulatory Properties of Fractionated Crude Extracts of Alternaria alternata

Kubheka,

Ndlovu,

Mkhwanazi

2024

Microorganisms

View full text Add to dashboard Cite

show abstract

A Step Towards Optimization of Amide-Linked Coumarin Pharmacophore: As an Anti-HIV Agent

Joshi,

Kumar,

Purohit

et al. 2024

CHR

View full text Add to dashboard Cite

The aim of the present investigation is to identify effective anti-HIV drugs through the in-silico virtual screening of the coumarin pharmacophore with or without substituents. Virtual screening started with target identification through computation docking and interactions, binding affinity through molecular dynamics, and the ADMET profile through the use of various enzymes. The target study suggests that the target is involved in various stages of HIV replication and in determining the ways in which non-nucleoside reverse transcriptase inhibitors (RTIs) influence it. The interaction pattern and simulation study conclude the specific affinity of coumarin pharmacophore to the HIV's reverse transcriptase enzyme, especially 3HVT. Moreover, the amide linkage worked as a synergistic bridge to provide more interaction to the pharmacophore. The initial results led to the determination of 83 virtual amide-like molecules, which were screened through docking and MD studies (100 ns) on the best-suited enzyme HIV's reverse transcriptase enzyme, such as PDB ID “3HVT”. The virtual screening study revealed the high affinity of compounds 7d and 7e with the lowest IC50 values of 0.729 and 0.658 μM; moreover, their metabolism pattern study, toxicity, and QED values in a range of 0.31-0.40 support a good drug candidate. The two compounds were also synthesized and characterized for future in vitro and in vivo studies. The in silico-based descriptor of compounds 7d and 7e indicates the potential future and provides the best two molecules and their synthetic route for the development of a more effective drug to combat HIV/AIDS epidemics.

show abstract

Bioinspired Pyrano[2,3-f]chromen-8-ones: Ring C-Opened Analogues of Calanolide A: Synthesis and Anti-HIV-1 Evaluation

Cited by 2 publications

References 46 publications

Anti-HIV Activity and Immunomodulatory Properties of Fractionated Crude Extracts of Alternaria alternata

Anti-HIV Activity and Immunomodulatory Properties of Fractionated Crude Extracts of Alternaria alternata

A Step Towards Optimization of Amide-Linked Coumarin Pharmacophore: As an Anti-HIV Agent

Contact Info

Product

Resources

About