Design, synthesis and evaluation of naphthalene-2-carboxamides as reversal agents in MDR cancer

A novel class of molecules with structure N-[3-(4-substituted-1-piperazinyl) propyl]-6-methoxy naphthalene-2-carboxamides were designed by generating a pharmacophore for potent MDR reversal activity, using Elacridar (GF 120918) as a query molecule and using MOE software. They were synthesized by condensing 6-methoxynaphthalene-2-carboxylic acid with N-[3-(4-substituted-1-piperazinyl) propyl] amines in the presence of DCC in DMF. They were evaluated in P388 murine lymphocytic leukemia cell line (P388) in vitro using SRB assay for cytotoxicity and in adriamycin-resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Test compounds were non-toxic at the doses studied (upto 80 μg/ml). They effectively reversed adriamycin resistance at the doses studied (40 and 80 μg/ml). The percentage enhancement in adriamycin activity was in the range 33.58 −90.67 (at 40 μg/ml) and 8.80–46.04 (at 80 μg/ml) and the corresponding reversal potency values were in the range 1.33–1.90 and 1.08–1.46, respectively. Test compounds 2, 3, and 5 exhibited better activity as compared to the standard resistant reversal agent (Verapamil), at same concentration.

Novel six compounds with structure N-[3-(4-substituted-1-piperazinyl) propyl]-6-methoxy naphthalene-2-carboxamides were designed, synthesized, and evaluated for MDR reversal activity by MTT assay. Test compounds reversed adriamycin resistance and compounds 2, 3, and 5 exhibited better activity as compared to Verapamil.Figure optionsDownload as PowerPoint slide