Abstract

Zidovudine (ZDV) and efavirenz (EFV), which belong to two separate classes of antiretroviral drugs, viz., NRTI and NNRTI, respectively, were subjected to different stability test conditions alone and in solid mixtures to evaluate possibility of interaction among them. The exposed samples were analyzed by high performance liquid chromatography (HPLC) using a C18 column and a PDA detector. Two new peaks were observed in the sample in which 50 μl CH3CN was added to increase the contact among the drugs, and which was subjected in open beaker to accelerated stability test condition of 40 °C/75%RH for 15 d. Subsequently, liquid chromatography-high resolution mass spectrometric (LC-HRMS) studies were carried out to obtain their accurate mass. The products were also isolated, and subjected to 1H, 13C, DEPT-135, COSY, HSQC and HMBC nuclear magnetic resonance (NMR) studies. The collective information allowed their structural characterization as isomeric cycloaddition products of the two drugs. As these were novel compounds, they were subjected to testing for cytotoxicity and in vitro anti-HIV-1 activity against primary isolates HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C) in TZM-bl cell line. The two were found to show weak activity against the standard drugs. The reason was sought through molecular docking studies, which highlighted that it was perhaps their comparative bigger molecular size than the drugs of both classes used currently in HIV therapy. Being previously unknown molecules, their in silico physicochemical and ADMET properties were also evaluated using ADMET Predictor™ and TOPKAT software.