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Journal ArticleDOI

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

Irena Kostova, S. Raleva, P. Genova1, Radka Argirova 
01 Jan 2005-Biotechnology & Biotechnological Equipment (Taylor & Francis)-Vol. 19, Iss: 1, pp 16-22

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.

AbstractThe 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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Citations
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Journal ArticleDOI
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.

18 citations


Cites background from "Recent Advances in the Discovery an..."

  • ...Coumarins and bicoumarins are widely spread in nature [1, 2]....

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Journal ArticleDOI
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...

18 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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Journal ArticleDOI
07 Mar 2011
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.

10 citations


Journal ArticleDOI
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.

3 citations


Journal ArticleDOI
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.

2 citations


References
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Journal ArticleDOI
TL;DR: Calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain, which was of particular interest since the A17 virus is highly resistant to previously known HIV- 1 specific, non-nucleoside RT inhibitors.
Abstract: Eight new coumarin compounds (1-8) were isolated by anti-HIV bioassay-guided fractionation of an extract of Calophyllum lanigerum. The structures of calanolide A (1), 12-acetoxycalanolide A (2), 12-methoxycalanolide A (3), calanolide B (4), 12-methoxycalanolide B (5), calanolide C (6) and related derivatives 7 and 8 were solved by extensive spectroscopic analyses, particularly HMQC, HMBC, and difference NOE NMR experiments. The absolute stereochemistry of calanolide A (1) and calanolide B (4) was established by a modified Mosher's method. Calanolides A (1) and B (4) were completely protective against HIV-1 replication and cytopathicity (EC50 values of 0.1 microM and 0.4 microM, respectively), but were inactive against HIV-2. Some of the related compounds also showed evidence of anti-HIV-1 activity. Studies with purified bacterial recombinant reverse transcriptases (RT) revealed that the calanolides are HIV-1 specific RT inhibitors. Moreover, calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain. This was of particular interest since the A17 virus is highly resistant to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise a structurally diverse but apparently common pharmacologic class. The calanolides represent a substantial departure from the known class and therefore provide a novel new anti-HIV chemotype for drug development.

510 citations


Journal ArticleDOI
TL;DR: Many compounds of plant origin that inhibit different stages in the replication cycle of human immunodeficiency virus (HIV) have been identified and only a very few of these plant-derived anti-HIV products have been used in a limited number of patients suffering from AIDS.
Abstract: Many compounds of plant origin have been identified that inhibit different stages in the replication cycle of human immunodeficiency virus (HIV): 1) virus adsorption: chromone alkaloids (schumannificine), isoquinoline alkaloids (michellamines), sulphated polysaccharides and polyphenolics, flavonoids, coumarins (glycocoumarin, licopyranocoumarin) phenolics (caffeic acid derivatives, galloyl acid derivatives, catechinic acid derivatives), tannins and triterpenes (glycyrrhizin and analogues, soyasaponin and analogues); 2) virus-cell fusion: lectins (mannose- and N-acetylglucosamine-specific) and triterpenes (betulinic acid and analogues); 3) reverse transcription: alkaloids (benzophenanthridines, protoberberines, isoquinolines, quinolines), coumarins (calanolides and analogues), flavonoids, phloroglucinols, lactones (protolichesterinic acid), tannins, iridoids (fulvoplumierin) and triterpenes; 4) integration: coumarins (3-substituted-4-hydroxycoumarins), depsidones, O-caffeoyl derivatives, lignans (arctigenin and analogues) and phenolics (curcumin); 5) translation: single chain ribosome inactivating proteins (SCRIP's); 6) proteolytic cleavage (protease inhibition): saponins (ursolic and maslinic acids), xanthones (mangostin and analogues) and coumarins; 7) glycosylation: alkaloids including indolizidines (castanospermine and analogues), piperidines (1-deoxynojirimicin and analogues) and pyrrolizidines (australine and analogues); 8) assembly/release: naphthodianthrones (hypericin and pseudohypericin), photosensitisers (terthiophenes and furoisocoumarins) and phospholipids. The target of action of several anti-HIV substances including alkaloids (O-demethyl-buchenavianine, papaverine), polysaccharides (acemannan), lignans (intheriotherins, schisantherin), phenolics (gossypol, lignins, catechol dimers such as peltatols, naphthoquinones such as conocurvone) and saponins (celasdin B, Gleditsia and Gymnocladus saponins), has not been elucidated or does not fit in the proposed scheme. Only a very few of these plant-derived anti-HIV products have been used in a limited number of patients suffering from AIDS viz. glycyrrhizin, papaverine, trichosanthin, castanospermine, N-butyl-1-deoxynojirimicin and acemannan.

403 citations


Journal ArticleDOI
TL;DR: As part of a search for novel inhibitors of HIV-1 reverse transcriptase, the acetone extract of the giant African snail, Achatina fulica, was shown to be active and 11 compounds of the inophyllum class were isolated, indicating certain structural requirements in the chromanol ring.
Abstract: As part of a search for novel inhibitors of HIV-1 reverse transcriptase, the acetone extract of the giant African snail, Achatina fulica, was shown to be active. Fractionation of the extract yielded inophyllums A, B, C, and E and calophyllolide (1a, 2a, 3a, 3b, and 6), previously isolated from Calophyllum inophyllum Linn., a known source of nutrition for A. fulica. From a methanol/methylene chloride extract of C. inophyllum, the same natural products in considerably greater yield were isolated in addition to a novel enantiomer of soulattrolide (4), inophyllum P (2b), and two other novel compounds, inophyllums G-1 (7) and G-2 (8). The absolute stereochemistry of inophyllum A (1a) was determined to be 10(R), 11(S), 12(S) from a single-crystal X-ray analysis of its 4-bromobenzoate derivative, and the relative stereochemistries of the other inophyllums isolated from C. inophyllum were established by a comparison of their 1H NMR NOE values and coupling constants to those of inophyllum A (1a). Inophyllums B and P (2a and 2b) inhibited HIV reverse transcriptase with IC50 values of 38 and 130 nM, respectively, and both were active against HIV-1 in cell culture (IC50 of 1.4 and 1.6 microM). Closely related inophyllums A, C, D, and E, including calophyllic acids, were significantly less active or totally inactive, indicating certain structural requirements in the chromanol ring. Altogether, 11 compounds of the inophyllum class were isolated from C. inophyllum and are described together with the SAR of these novel anti-HIV compounds.

331 citations


Journal ArticleDOI
TL;DR: Calophyllum cerasiferum contained (-)-calanolide B as its major coumarin constituent in significant amount and thus constitute a renewable source of this compound.
Abstract: The seeds of Calophyllum cerasiferum Vesque (Family-Clusiaceae), and Calophyllum inophyllum Linn. (Family-Clusiaceae) contain several known coumarins, among which were the potent HIV reverse transcriptase inhibitors costatolide and inophyllum P. Calophyllum cerasiferum contained (-)-calanolide B as its major coumarin constituent in significant amount and thus constitute a renewable source of this compound.

264 citations


Journal ArticleDOI
TL;DR: The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol, which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy- 2-methylbutan-2-ol, cyclization, and Luche reduction.
Abstract: The anti-HIV agent (±)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [→ 5 → 6 → 11 → 18 → (±)-1], which includes Pechmann reaction, Friedel−Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (±)-1. Reduction of chromone 12, synthesized by Kostanecki−Robinson reaction from chromene 11, failed to afford (±)-1. The synthetic (±)-1 has been chromatographically resolved into its optically active forms, (+)- and (−)-1. The anti-HIV activities for synthetic (±)-1, as well as resultant (+)- and (−)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (−)-1 was inactive.

165 citations