Synthesis of pro-apoptotic indapamide derivatives as anticancer agents

Abstract

<div><p></p><p>4-Chloro-3-({[(substitutedamino)carbonothioyl]amino}sulfonyl)-<i>N</i>-(2-methyl-2,3-dihydro-1<i>H-</i>indole-1-yl)benzamide (<b>1</b>–<b>20</b>) and 4-chloro-3-({[3-(substituted)-4-oxo-1,3-thiazolidine-2-ylidene]amino}sulfonyl)-<i>N</i>-(2-methyl-2,3-dihydro-1<i>H</i>-indole-1-yl)benzamide derivatives (<b>21</b>–<b>31</b>) were synthesized from 4-chloro-<i>N</i>-(2-methyl-2,3-dihydroindol-1-yl)-3-sulfamoylbenzamide (indapamide). 4-Chloro-3-({[(4-chlorophenyl) amino) carbonothioyl]amino}sulfonyl)-<i>N</i>-(2-methyl-2,3-dihydro-1<i>H-</i>indole-1-yl)benzamide <b>12</b> demonstrated the highest proapoptotic activity among all synthesized compounds on melanoma cell lines MDA–MB-435 with 3.7% growth inhibition at the concentration of 10 µM. Compound <b>12</b> (<b>SGK 266</b>) was evaluated <i>in vitro</i> using the MTT colorimetric method against melanoma cancer cell line MDA–MB435 growth inhibition for different doses and exhibited anticancer activity with IC₅₀ values of 85–95 µM against melanoma cancer cell line MDA–MB435. In addition, this compound was investigated as inhibitors of four physiologically relevant human carbonic anhydrase isoforms, hCA I, II, IX and XII. The compund inhibited these enzymes with IC₅₀ values ranging between 0.72 and 1.60 µM.</p></div