Recent Advances in the Discovery and Development of Plant-Derived Natural Coumarins and their Analogues as Anti Human Immunodeficiency Virus—Type 1 (HIV-1) Agents
TL;DR: The aim of this review is to summarize research findings for herbal medicines, especially coumarins, which are endowed with the ability to inhibit HIV.
Abstract: The acquired immunodeficiency syndrome (AIDS) is a result of human immunodeficiency virus (HIV) infection which leads to severe suppression of immune functions. AIDS is a real threat to the health of mankind, and the search for effective therapies is still of great importance. However, besides the high cost, there are adverse effects and limitations associated with chemotherapy applied. Thus, herbal medicines are frequently used as an alternative therapy by individuals living with HIV. Numerous plant-derived compounds have been evaluated for inhibitory effects on HIV replication, and many coumarins have been found to inhibit different steps in HIV replication cycle. The aim of this review is to summarize research findings for herbal medicines, especially coumarins, which are endowed with the ability to inhibit HIV.
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TL;DR: In this article, a review of antibiotic resistance strategies produced by multidrug-resistant bacteria and phytochemicals from different classes with documented antimicrobial action against resistant bacteria, either alone or in combination with traditional antibiotics is presented.
Abstract: Microbial resistance has progressed rapidly and is becoming the leading cause of death globally. The spread of antibiotic-resistant microorganisms has been a significant threat to the successful therapy against microbial infections. Scientists have become more concerned about the possibility of a return to the pre-antibiotic era. Thus, searching for alternatives to fight microorganisms has become a necessity. Some bacteria are naturally resistant to antibiotics, while others acquire resistance mainly by the misuse of antibiotics and the emergence of new resistant variants through mutation. Since ancient times, plants represent the leading source of drugs and alternative medicine for fighting against diseases. Plants are rich sources of valuable secondary metabolites, such as alkaloids, quinones, tannins, terpenoids, flavonoids, and polyphenols. Many studies focus on plant secondary metabolites as a potential source for antibiotic discovery. They have the required structural properties and can act by different mechanisms. This review analyses the antibiotic resistance strategies produced by multidrug-resistant bacteria and explores the phytochemicals from different classes with documented antimicrobial action against resistant bacteria, either alone or in combination with traditional antibiotics.
48 citations
TL;DR: The objective of this review is to evaluate data on coumarins’ potent activity with respect to the inhibition of HIV-reverse transcriptase, HIV-integrase or HIV-protease.
Abstract: Considerable progress has been made in recent years in the field of drug development against HIV. Many different kinds of natural products, including coumarins, have been found to be active in anti-HIV models and are thus undergoing further investigation. This review demonstrates the variety of coumarins with unique mechanisms of action in the different stages of HIV replication. The discovery and development of coumarins as anti-HIV agents has expanded in the past two decades. Most of the studies have been focused on the inhibitory activity of reverse transcriptase, but anti-integrase and antiprotease activities were also described. The objective of this review is to evaluate data on coumarins’ potent activity with respect to the inhibition of HIV-reverse transcriptase, HIV-integrase or HIV-protease. Recent requirements for potential anti-HIV agents increasingly require adequate definition of the mechanism of action as well as definition of toxic effects and this also applies to natural as well as synthe...
21 citations
Cites background from "Recent Advances in the Discovery an..."
...1 μM* RT [4,5]...
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...3 μM¶,# RT [4,5]...
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...2 μM*,‡,§ RT [4,5]...
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...The coumarins represent a unique class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) [4,5]....
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...Imperatorin 100 μg/ml** RT [4,5]...
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TL;DR: The cerium Ce(III, lanthanum La(III), and neodymium Nd(III) complexes were synthesized and studied for the first time for cytotoxicity (on MT-2 cells) and as anti-HIV agents under acute and chronic infection.
Abstract: The cerium Ce(III), lanthanum La(III), and neodymium Nd(III) complexes with 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (warfarin) (W) and 3,3'-benzylidenebis[4-hydroxycoumarin] (1) were synthesized and studied for the first time for cytotoxicity (on MT-2 cells) and as anti-HIV agents under acute and chronic infection. The complexes were characterized by different physicochemical methods: mass spectrometry, (1)H NMR, (13)C NMR, and IR spectroscopy. The spectra of the complexes were interpreted on the basis of comparison with the spectrum of the free ligands. Anti-HIV effect of the complexes/ligands was measured in MT-2 cells by microtiter infection assay. Detection of endogenous reverse transcriptase (RT) activity and RT processivity by PCR indicative for proviral DNA synthesis demonstrated that anti-HIV activity has not been linked to early stages of viral replication. No effect on late steps of viral replication has been found using cells chronically producing HIV-1(LAI) virus. La(W) demonstrated anti-HIV activity (IC50=21.4 muM) close to maximal nontoxic concentration. Nd(W), Ce(1), and Nd(1) demonstrated limited anti-HIV potency, so none of the complexes seems appropriate to be used in clinic. Further targeting of HIV-1 inhibition by La(W) is under progress.
20 citations
Cites background from "Recent Advances in the Discovery an..."
...Coumarins and bicoumarins are widely spread in nature [1, 2]....
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07 Mar 2011
TL;DR: In this article, a new reaction in phosphorus chemistry, namely, the interaction of 2,2,2-trihalobenzo-1, 3, 2-dioxaphospholes with aryl(alkyl)acetylenes, leads to the formation of benzo[e]-1,2oxaphosphinine derivatives, or “phosphacoumarins.
Abstract: The account covers a new reaction in phosphorus chemistry, namely, the interaction of 2,2,2-trihalobenzo-1,3,2-dioxaphospholes with aryl(alkyl)acetylenes, which leads to the formation of benzo[e]-1,2-oxaphosphinine derivatives, or “phosphacoumarins.” The easy formation of a P-C bond and phosphoryl group, the ipso-substitution of the oxygen atom by the carbon one, and selective chlorination para to endocyclic oxygen are realized under mild conditions in this reaction. The ipso-substitution of a tertiary butyl group and a bromine atom also takes place in some cases.
11 citations
TL;DR: In this article, the minor isomer was formed as a result of substitution of the oxygen atom in the ortho position with respect to one tert-butyl group of the initial phosphole.
Abstract: 2,2,2-Tribromo-4,6-di-tert-butylbenzo-1,3,2λ5-dioxaphospholedioxaphosphole reacted with a terminal alkyne, pent-1-yne, to give a mixture of two isomeric 1,2-benzoxaphosphinine derivatives, 6,8- and 5,7-di-tert-butyl-2-bromo-4-propylbenzo-1,2λ5-oxaphosphinin-2-oxides, at a ratio of 5.9: 1. The regioselectivity of substitution of oxygen in the dioxaphosphole fragment by carbon differs from that observed previously in the reaction with 4,6-di-tert-butyl-2,2,2-trichlorobenzo-1,3,2λ5-dioxaphosphole: the minor isomer was formed as a result of substitution of the oxygen atom in the ortho position with respect to one tert-butyl group of the initial phosphole.
3 citations
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TL;DR: Tissue culture results indicated that the combination of (+)-calanolide A and nevirapine possessed an additive to weakly synergistic effect in blocking replication of HIV-1 in tissue culture, suggesting that (+)-Calanolide B and ne virapine might have rationale as a combination therapy for HIV disease.
Abstract: We have tested both wild-type and drug-resistant mutated, recombinant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) molecules for sensitivity to each of two non-nucleoside ...
22 citations
TL;DR: Buds of this species contained large quantities of pyranocoumarins and a small amount of sitosterol, indicating that the coumarin-synthesising tissues are mainly located at the non woody young plant parts of C. cordato-oblongum.
19 citations
Journal Article•
TL;DR: Takeaway is that (+)-calanolide A, the most potent in the series of calanolide compounds, is undergoing clinical investigation for safety and efficacy in HIV-infected individuals and inclusion in a combination therapy may be clinically beneficial.
Abstract: Both naturally occurring and semi-synthetic calanolide compounds are potent anti-human immunodeficiency virus (HIV) agents. In fresh human cells, they are highly effective inhibitors against low passage clinical virus strains, including those representative of the various HIV-1 clade strains (A through F), syncytium-inducing (SI) and non-syncytium-inducing (NSI) isolates, and T-tropic and monocyte-tropic isolates. These compounds also exhibit an enhanced antiviral activity against one of the most prevalent non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant viruses that is engendered by the Y181C amino acid change in reverse transcriptase (RT). Further enhancement of activity is observed with RTs that possess the Y181C change together with AZT-resistant mutations. Moreover, when challenged with viruses containing Y181C and K103N dual mutations, calanolide compounds remain active. These dual mutations are highly resistant to all approved NNRTIs (eg, delavirdine, nevirapine and efavirenz). In cell culture assays, calanolide compounds, especially (+)-calanolide A, select primarily resistant viruses possessing the T139I amino acid change. This mutation appears to be unique to calanolides since it remains susceptible to other NNRTIs. Synergistic effects are observed in both cultured cells and animal models when calanolides are used in combination with other anti-HIV agents. Enzymatic analyses indicate that calanolides inhibit HIV-1 RT through a mechanism that affects both the Km for normal substrate dTTP and the Vmax, resulting in a mixed-type inhibition, which is different from that of other known NNRTIs. Two possible binding modes/sites at the HIV-1 RT enzyme have been suggested for (+)-calanolide A. Taken together, the calanolide compounds represent a novel and distinct subgroup of the NNRTI family and inclusion of a calanolide in a combination therapy may be clinically beneficial. Of particular interest is the use of calanolide in the treatment of patients who have failed other NNRTI therapy and developed the Y181C mutation or the Y181C/K103N dual mutations. Currently, (+)-calanolide A, the most potent in the series of calanolide compounds, is undergoing clinical investigation for safety and efficacy in HIV-infected individuals.
19 citations
TL;DR: A new coumarin identified as 5-hydroxy-6-methoxy-7-(3-methyl-but-2-enyloxy)-2H-1-benzopyran- 2-one (isoobtusitin) was isolated from Psiadia dentata and showed a moderate inhibitory activity against poliovirus and a very weak activity against (HIV).
Abstract: A new coumarin identified as 5-hydroxy-6-methoxy-7-(3-methyl-but-2-enyloxy)-2H-1-benzopyran-2-one (isoobtusitin) was isolated from Psiadia dentata. This compound showed, in vitro, a moderate inhibitory activity against poliovirus and a very weak activity against (HIV), whereas it was inactive against (HSV1), (VSV), and murine tumoral cell lines (3LL, L1210).
18 citations
TL;DR: This is the first report of a validated HPLC assay for determination of (+)-calanolide A concentrations in rat and dog plasma as well as human plasma obtained from clinical trials.
7 citations