2. AZT = Azidothymidine (3’-azido-3’-deoxythymidine, Zidovudine)
Acts as inhibitor of intracellular enzyme known as reverse transcriptase, responsible for utilizing viral RNA to generate a copy of DNA with appropriate code to generate new virus.

4. Treatment of HIV
When HIV replicates (makes new copies of itself) it often makes mistakes.
Taking two or more antiretrovirals at the same time vastly reduces the rate at which resistance develops
The term Highly Active Antiretroviral Therapy (HAART) is used to describe a combination of three or more anti-HIV drugs.

5. Treatment of HIV Current classes of antiretroviral drugs include:
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Non-Nucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Fusion or Entry Inhibitors
Integrase Inhibitors

6. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
These were the first type of drug available to treat HIV infection in 1987.
NRTIs (also known as nucleoside analogues or nukes) interfere with the action of an HIV protein called reverse transcriptase, which the virus needs to make new copies of itself.
NRTIs are sometimes called the "backbone" of combination therapy because most regimens contain at least two of these drugs.

7. zidovudine/Retrovir(AZT, ZDV) didanosine/Videx, Videx EC (ddI)
Antiretroviral Agents Currently Available (generic name/Trade name) Nucleoside Analogs (NRTI’s)
zidovudine/Retrovir(AZT, ZDV)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
stavudine/Zerit (d4T)
lamivudine/Epivir (3TC)
abacavir/Ziagen (ABC)

8. Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)
didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC)
Zidovudine/Retrovir
(AZT, ZDV)

9. The AZT works by interfering with reverse transcription, as shown in the LINK, but must first be converted to the triphosphate
Link

10. Since phosphates are charged at neutral pH, and thus do not cross the cell membrane, suitably protected phosphate derivatives might serve as ‘prodrugs’ which can be hydrolytically cleaved once inside the cell.

11. Thus it was desired to prepare phosphate esters which would be rapidly chemically hydrolyzed at neutral pH. Two types of phosphate esters were explored:

13. However, neither of these approaches worked, since the hydrolysis always stops at the (negatively charged) phosphodiester level

14. The problem was solved by protecting the two phosphate esters differently, one as a phenyl ester, and one as a benzyl ester, through use of a cyclic diester derivative of salicylic acid.

15. Note that the phenyl ester will be hydrolytically cleaved quickly, followed by slower cleavage of the benzyl ester. However, the intermediate phenol can serve as a proton donor, and, as a negatively charged phenolate anion, also serves to activate the leaving of the phosphate in an Sn1 fashion.