ChemInform Abstract: A New Class of Anti-HIV Agents: Synthesis and Activity of Conjugates of HIV Protease Inhibitors with a Reverse Transcriptase Inhibitor.

Background: Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1. Methods: Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil by other functional groups or N1-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil. Results: These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.067 and 0.069 μM) and selective (selectivity index =685 and 661), respectively. Structure–activity relationships among the newly synthesized uracil analogues suggest the importance of the H-bond formed between 6-amino group of 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil and amide group of HIV-1 reverse transcriptase. Conclusions: We discovered two 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl) uracils, (6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil) as novel anti-HIV agents. These compounds should be further pursued for their toxicity and pharmacokinetics in vivo as well as antiviral activity against non-nucleoside reverse transcriptase inhibitor-resistant strains.

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‘Double-drugs’— A new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(00)00202-x ◽

2000 ◽

Vol 10 (11) ◽

pp. 1227-1231 ◽

Cited By ~ 16

Author(s):

Hikaru Matsumoto ◽

Tomonori Hamawaki ◽

Hisashi Ota ◽

Tooru Kimura ◽

Toshiyuki Goto ◽

...

Keyword(s):

Protease Inhibitor ◽

Reverse Transcriptase ◽

Transcriptase Inhibitor ◽

Hiv Protease ◽

Hiv Protease Inhibitor ◽

New Class ◽

Reverse Transcriptase Inhibitor

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HIV protease inhibitors: weapons in the war against HIV/AIDS

Hallelujah Moments ◽

10.1093/oso/9780190080457.003.0004 ◽

2020 ◽

pp. 39-60

Author(s):

Eugene H. Cordes

Keyword(s):

Reverse Transcriptase ◽

Protease Inhibitors ◽

Basic Research ◽

Transcriptase Inhibitor ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Structure Based Drug Design ◽

Infective Disease ◽

Act Up ◽

Hiv Aids

The discovery of drugs for AIDS has converted these infections from a death sentence into a chronic infectious disease. The research of Luc Montagnier and Robert Gallo established that HIV is the cause of AIDS, subsequently known as HIV/AIDS, the most deadly infective disease known. Basic research into the life cycle of HIV revealed a number of potential molecular targets for treatment of the infection. Among these are HIV protease and reverse transcriptase, enzymes required for the propagation of the virus in human T cells. AZT (azidothymidine), a reverse transcriptase inhibitor, was the first drug approved for treatment of HIV/AIDS. It was followed by three HIV protease inhibitors: saquinavir, ritonavir, and indinavir (Incivek). The last of these was discovered through a structure-based drug design strategy and proved to be a turning point in therapy for HIV/AIDS. This drug discovery effort was conducted in an atmosphere of prejudice, ignorance, snake oil medicine, and intense activism by Act Up and others. The net result is a miracle of modern medicine.

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