Twelve out of the top twenty drugs are derived from natural products.

       The identification of human immunodeficiency virus (HIV) as the cause of acquired immune deficiency syndrome (AIDS).  Since the discovery of azidothymidine, HIV chemotherapy has been dominated by neucloside reverse transcriptase inhibitors derived from 2’,3’-dideoxynucleosides such as azidothymidine (AZT), didanosine, zalcitabine, stavudine and lamivudine .  The HIV protease inhibitors, saquinavir, ritanovir, indinavir and neflinavir have also become available.  These agents can extend the life of an AIDS patient, but none can cure the disease.  Further these are associated with serious side effects such as bone marrow formation, acute pancreatitis and hepatotoxicity.  Long term treatment with all these agents has led to drug resistant HIV strains.  Therefore the need for new candidate compounds with improved selectivity and activity for anti-HIV is  assumed importance . One important enzyme target for anti-HIV drugs is reverse transcriptase.

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                   Non nucleoside reverse transcriptase inhibitors are now emerging as important agents.  The coumarin derivatives isolated from tropical plant Calophyllum species (+)-calanolide A, (-)-calanolide B and ionophyllum B are now emerging as the most potent anti-HIV reverse transcriptase inhibitor agents (L.A.Sorbera et al, Calanolide A in “Drugs of the future”,  1999, 24 (3), 235).

                      (+)- Calanolide A was found to inhibit, in in vitro, laboratory and clinical strains of HIV – isolates.  This agent  completely inhibited both AZT-resistant strains and pyridinone resistant strains.  This agent is also shown to inhibit HIV-1 reverse transcriptase at concentration of 200 mcg/ml. Pharmocokinetics and toxicity studies were also made on (+)-calonolide A.

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                     Phase I clinical studies on 47 HIV-negative healthy volunteers was carried out to generate the bioavailability and toxicity data.  At present  phase II clinical trials dose ranging studies involving HIV positive patients with no previous antiretroviral therapy is in progress.

                      (+)- Calanolide A is a 5,7-dioxygenated coumarin with a propyl substituent at position-4 of coumarin nucleus.  Further at positions 7,8 of coumarin nucleus, a saturated pyran ring is fused while at positions 5,6 a 2,2-dimethyl pyran ring is fused.

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                         Another natural coumarin, isolated from the latex of the Malaysian plant, Calophyllum  teysmannii var inophylloide, which possesses anti-HIV-1 activity, is costatolide. It is a stereoisomer of (+)- calanolide A and calanolide B.  Its anti-HIV- 1 activity is intermediate between the two isomers calanolide A and calanolide-B (Fuller et al, HIV- Inhibitors coumarins from the latex of the tropical rain forest tree Calophyllum teysmanni var inophylloide, Biorg. Med. Chem. Lett., 1994  4 (16),1961).  The activity of calonolide B is also reported (Annual Drug Data  Report, 1994, 16(3), 290) .

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                        Inophyllum B, a 4-phenyl coumarin isolated from Malaysian tree, Calophyllum inophyllum and the giant African snail Achantia fulica is a potent inhibitor of HIV-1 reverse transcriptase.  It is a 4-phenyl coumarin with a dihydropyran fused  at 7,8 and 2,2-dimethyl dihydropyran fused at 5,6.  Its stereoisomer, inophyllum-P, also showed similar activity in the bioassays [A.D. Patel et al  The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from Malaysian tree Calophyllum inophyllum, J.Med.Chem. 1993, 36(26)4131].

                     Thus synthesis of  a number of 4-alkyl coumarins and 4-phenyl coumarins  related  to calanolides will be rewarding. Further screening  of other  calophyllum  species available in India  may lead to discovery of new HIV-1 reverse transcriptase  inhibitors useful as anti AIDS agents.
 
 
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