Synthesis and in Vitro Antibacterial Activity of Novel 5′-O-Analog Derivatives of Zidovudine as Potential Prodrugs

Abstract

An efficient, short synthesis of four potential prodrugs of 3'-azido-3'-deoxythymidine (AZT) and their antibacterial activity are reported. The 5'-OH group of AZT was functionalized with oxalyl chloride obtaining an acyl chloride derivative (AZT-Ox), which by further transformation with leucine, isoleucine and valine amino acids led to the corresponding AZT analogs, namely AZT-Leu, AZT-iLeu and AZT-Val. A carboxyl acid derivative (AZT-Ac) was also obtained by hydrolysis of AZT-Ox. These compounds, which exhibit anti HIV activity, have killed collection and clinical strains of some opportunistic infectious agents in AIDS-related complex. Thus, the clinical strains, K. oxytoca, S. typhi and K. pneumoniae, and collection strain K. pneumoniae ATCC 10031 showed sensitivity to antibiotics. The activity order for the studied compounds against the most sensitive strain (K. pneumoniae ATCC 10031) was AZT-Leu > AZT-iLeu > AZT-Val > AZT-Ac > AZT. On the other hand, the activity order for the second most sensitive strain (K. oxytoca) was AZT-Leu > AZT-Val = AZT-Ac > AZT-iLeu > AZT. The most effective antibacterial drug AZT-Leu, M.I.C.=0.125 microgmL(-1)) was 16 times more active than AZT (AZT, M.I.C.=2 microg mL(-1)) against K.

In-utero triple antiretroviral exposure associated with decreased growth among HIV-exposed uninfected infants in Botswana

“…This was in keeping with Botswana national treatment guidelines at the time each study was conducted. Direct ingestion of ZDV by children may have provided protection against bacterial pathogens responsible for diarrhoeal disease and pneumonia, as ZDV has antibacterial properties [22–24] and illnesses in infancy and childhood have been associated with poor growth [25]. However, analyses of hospitalizations for respiratory disease and diarrhoeal illness between the two groups did not reveal any significant differences (data not shown) and mortality was not significantly different between the two groups.…”

Stability and plasmatic protein binding of novel zidovudine prodrugs: Targeting site ii of human serum albumin

“…In this way many prodrugs have been prepared by derivatizing the 5´OH of AZT in order to obtain inactive compounds requiring a chemical and/or enzymatic hydrolytic step prior to exhibiting bioactivity.In line with these efforts, we have previously reported the obtention of prodrugs of AZT linking ester and amide moieties at the 5´OH position to obtain both "single" and "double" prodrugs. [14][15][16][18][19][20][21] As an example, oxalic acid (AZT-Ox) was used as linker chain between AZT and different essential aminoacids…”

“…Although some of these prodrugs showed promising biological activities as measured in anti HIV in vitro assays, [19] they had a poor resistance to chemical and enzymatic hydrolysis, which was also accompanied by a limited bound fraction to HSA. [6,[22][23][24][25] Recently, we reported the synthesis and chemical stability evaluation of three novel prodrugs of AZT obtained by derivatization with different dicarboxylic acids (1-3, Figure 1.c): succinic (1), glutaric (2) and adipic (3) acids.…”

Synthesis and antiretroviral evaluation of derivatives of zidovudine

“…18,22,23 The most characteristic In the IR spectra of 2-7 (KBr), absorptions at 2800 and 3100 cm -1 corresponding to C-H stretchings are observed, as well as characteristic feature of these molecules at 2100 cm -1 due to the asymmetric stretchings of the azido group. 18,22,23 The absorption bands around 1700 cm -1 arose from C=O and N-H of the pyrimidinic amide group stretchings, as in the case of the carbamate group stretchings of 4-7, appear as a broad band for some compounds. In the IR spectrum of 3, the absorption bands at 1300 and 1000 cm -1 representing the C-O-C vibrations were much more complex and pronounced in this spectrum than in AZT.…”