3′-Azido-3′-Deoxy-5′-O-Isonicotinoylthymidine, a New Prodrug of Zidovudine. Synthesis, Solid State Characterization and Anti Hiv-1 Activity

Abstract

Synthesis, solid state characterization and anti HIV-1 activity of 3'-azido-3'-deoxy-5'-O-isonicotinoylthymidine (2), a new prodrug of zidovudine (AZT, 1), are described. Two solid forms of 2 prepared by crystallization from ethyl acetate-petroleum ether (form alpha) and from a melt sample of form alpha (amorphous form) were characterized by X-ray diffractometry, infrared spectroscopy, differential scanning calorimetry (DSC) and thermogravimetry (TGA) techniques. The novel nucleoside exhibited antiviral activity against standard and resistant strain panels of HIV-1 as well as cytotoxicity similar to that of AZT.

Preformulation Studies of Zidovudine Derivatives: Acid Dissociation Constants, Differential Scanning Calorimetry, Thermogravimetry, X-Ray Powder Diffractometry and Aqueous Stability Studies

“…Regarding the crystallization properties of the studied compounds, it is interesting to note that a similar behavior was observed for other AZT esters [ 11 , 24 ], i.e. under similar crystallization conditions to those used with 2–6, some crystallized and others not.…”

“…Although nucleoside analogues continue to play a prominent role as antiviral agents [ 4 ], their therapeutic potential is often hampered by their poor biopharmaceutical properties [ 5 ]. Therefore, as part of our ongoing efforts to search for novel antiviral agents, we developed AZT derivatives with anti HIV activity, modifying the 5′-OH position of AZT which could form a reservoir of the drug in different human tissues, thus requiring less frequent dosing [ 6 – 11 ].…”

Conformational Studies of Novel Antiretroviral Analogs of Zidovudine

“…A phase angle P ¼ 0 corresponds to an absolute north conformation possessing a symmetrical twisted form 3 T 2 (C 3 0 -endo, C 2 0-exo), whereas its south antipode, 2 T 3 , is represented by P ¼ 180 (C 2 0endo, C 3 0 -exo). [11] Since one of the proposed inhibitory actions of the 2 0 ,3 0 -deoxynucleosides may be related to the preferred conformation of the modified furanose ring, [10] and taking into consideration that we have been involved in a research program aimed at exploring more convenient novel anti HIV-1 analogs of AZT, [14][15][16] the purpose of this paper was to perform the structural and conformational analyses of 3 0 -azido-3 0 -deoxy-5 0 -O-isonicotinoylthymidine (AZT-Iso, 2), (À)-trans-(5S,6S)-5-bromo-6,5 0epoxy-5,6-dihydro-3 0 -azido-3 0 -deoxythymidine [(À)-trans-(5S,6S), 3] and (þ)-trans-(5R,6R)-5-bromo-6,5 0 -epoxy-5,6-dihydro-3 0 -azido-3 0 -deoxythymidine [(þ)-trans-(5R,6R), 4], three novel derivatives of 1 (Fig. 3).…”

“…The superscripts and subscripts represent, respectively, the carbon atoms displaced above and below the plane relative to other atoms of the fivemember ring (Fig. 4) with proved anti HIV activity, [14][15][16] and its comparison with the prototype. [4,13] The maximum out-of-plane pucker value attained by any dihedral ring angle in a complete cycle of pseudorotation, is given by t max (t max ¼ C 1 0 -C 2 0 -C 3 0 -C 4 0 /cos P).…”

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.…”