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
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...1 μM* RT [4,5]...
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...3 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: Soulattrolide, a coumarin isolated from Calophyllum teysmannii latex, was found to be a potent inhibitor of HIV-1 reverse transcriptase (RT) with an IC50 of 0.34 microM.
Abstract: Soulattrolide (1), a coumarin isolated from Calophyllum teysmannii latex, was found to be a potent inhibitor of HIV-1 reverse transcriptase (RT) with an IC50 of 0.34 μM. Inhibition was remarkably specific, with no appreciable activity being observed toward HIV-2 RT, AMV RT, RNA polymerase, or DNA polymerases α or β.
63 citations
TL;DR: Chemical and biological studies of the latex exuded from trees of the genus Calophyllum found that calanolide A was not present in latex from the original source species, but a related coumarin, costatolide, was abundant in latex of C. teysmanii var.
62 citations
TL;DR: Comparison of cross-resistance data obtained with a panel of NNRTI-resistant virus strains suggests that a compound of the calanolide A series, such as costatolide, should be evaluated further for therapeutic use in combination with other anti-HIV agents.
Abstract: (+)-Calanolide A (NSC 650886) has previously been reported to be a unique and specific nonnucleoside inhibitor of the reverse transcriptase (RT) of human immunodeficiency virus (HIV) type 1 (HIV-1) (M J Currens et al, J Pharmacol Exp Ther, 279:645-651, 1996) Two isomers of calanolide A, (-)-calanolide B (NSC 661122; costatolide) and (-)-dihydrocalanolide B (NSC 661123; dihydrocostatolide), possess antiviral properties similar to those of calanolide A Each of these three compounds possesses the phenotypic properties ascribed to the pharmacologic class of nonnucleoside RT inhibitors (NNRTIs) The calanolide analogs, however, exhibit 10-fold enhanced antiviral activity against drug-resistant viruses that bear the most prevalent NNRTI resistance that is engendered by amino acid change Y181C in the RT Further enhancement of activity is observed with RTs that possess the Y181C change together with mutations that yield resistance to AZT In addition, enzymatic inhibition assays have demonstrated that the compounds inhibit RT through a mechanism that affects both the K(m) for dTTP and the V(max), ie, mixed-type inhibition In fresh human cells, costatolide and dihydrocostatolide are highly effective inhibitors of low-passage clinical virus strains, including those representative of the various HIV-1 clade strains, syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates Similar to calanolide A, decreased activities of the two isomers were observed against viruses and RTs with amino acid changes at residues L100, K103, T139, and Y188 in the RT, although costatolide exhibited a smaller loss of activity against many of these NNRTI-resistant isolates Comparison of cross-resistance data obtained with a panel of NNRTI-resistant virus strains suggests that each of the three stereoisomers may interact differently with the RT, despite their high degree of structural similarity Selection of viruses resistant to each of the three compounds in a variety of cell lines yielded viruses with T139I, L100I, Y188H, or L187F amino acid changes in the RT Similarly, a variety of resistant virus strains with different amino acid changes were selected in cell culture when the calanolide analogs were used in combination with other active anti-HIV agents, including nucleoside and nonnucleoside RT and protease inhibitors In assays with combinations of anti-HIV agents, costatolide exhibited synergy with these anti-HIV agents The calanolide isomers represent a novel and distinct subgroup of the NNRTI family, and these data suggest that a compound of the calanolide A series, such as costatolide, should be evaluated further for therapeutic use in combination with other anti-HIV agents
62 citations
TL;DR: Cordatolide A and B demonstrated IC(50) values of 19.3 and 11.7 microM, respectively, against HIV-1 replication in a novel green fluorescent protein (GFP)-based reporter cell assay (HOG.R5).
Abstract: As part of our continuing study on the Calophyllum species, a number of coumarins, xanthones and chromene acids from different Calophyllum species of Sri Lanka were tested for inhibitory activity against the HIV-1 and its virally-encoded reverse transcriptase (RT). These compounds were found to be inactive in both the HIV-1 RT and whole virus systems. In contrast, cordatolide A and B demonstrated IC(50) values of 19.3 and 11.7 microM, respectively, against HIV-1 replication in a novel green fluorescent protein (GFP)-based reporter cell assay (HOG.R5).
54 citations
Journal Article•
TL;DR: Calanolide A inhibited HIV-1 RT in a synergistic fashion with nevirapine, further distinguishing it from the general class of nonnucleoside RT inhibitors, and shares some binding domains with both phosphonoformic acid and 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil.
Abstract: Calanolide A, first isolated from the tropical rain forest tree Calophyllum lanigerum, is a potent human immunodeficiency virus type-1 (HIV-1) specific reverse transcriptase (RT) inhibitor, broadly active against diverse HIV-1 strains, including nucleoside and nonnucleoside-resistant variants. We examined the biochemical mechanism of inhibition of HIV-1 RT by calanolide A. Two template/primer systems were examined: ribosomal RNA and homopolymeric rA-dT 12-18. Calanolide A inhibited HIV-1 RT by a complex mechanism involving two calanolide A binding sites. With respect to either deoxynucleotide triphosphate (dNTP) or template/primer binding, one site was competitive and the other was uncompetitive. The data indicated that calanolide A bound near the active site of the enzyme and interfered with dNTP binding. Calanolide A inhibited HIV-1 RT in a synergistic fashion with nevirapine, further distinguishing it from the general class of nonnucleoside RT inhibitors. At certain concentrations, calanolide A bound HIV-1 RT in a mutually exclusive fashion with respect to both the pyrophosphate analog, phosphonoformic acid and the acyclic nucleoside analog 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil. This indicates that calanolide A shares some binding domains with both phosphonoformic acid and 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil, presumably reflecting that it interacts with RT near both the pyrophosphate binding site and the active site of the enzyme.
53 citations