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Cancer is a disease with fatal consequences; thus, searching for innovative compounds with anticancer properties remains an active pursuit. One of the highly promising candidates is a compound derived from 3-thiocyanato-1H-indoles. However, the number of derivative compounds is currently limited. A quantitative structure and activity relationship (QSAR) study was conducted on derivate compounds 3-thiocyanato-1H-indoles to establish equations that predict the anticancer activity of more effective derivatives. This study aims to compare the effectiveness of the AM1 (Austin Model 1), PM3 (Parameterized Model 3), and RM1 (Recife Model 1) semiempirical methods, which are new techniques implemented in the Hyperchem version 8.0. Twenty experimental data were used, 16 derivatives of 3-thiocyanate-1H-indoles as regression compounds (fitting) and four derivates as test compounds. QSAR analysis was performed based on multiple linear regression calculations on 3-thiocyanate-1H-indoles derivative compounds by plotting IC50 (µM) as the dependent variable and descriptors as the independent variable. The best QSAR equation was obtained from the AM1 semiempirical calculation method with the following equation: IC50 = -1.705 + 0.511(Delta) + 0.346(Dipol) + 18.287(qC9) – 0.645(Log P) + 13.952(qC6), with n =20; r =0.814; r2 =0.662; The standard error (SE) =1.044; Fcount/Ftable =1.851; PRESS =15.219.

A novel series of twenty 3-thiocyanato-1H-indoles, carrying diversification at positions N-1, C-2 and C-5 of the heterocyclic core, were synthesized; their antiproliferative activity against four human cancer cell lines (HL60, HEP-2, NCI-H292 and MCF-7) was evaluated, employing doxorubicin as positive control. Indole, N-methylindole and 2-(4-chlorophenyl)-N-methylindole demonstrated to be essentially inactive, whereas several of their congener 3-thiocyanato-1H-indoles displayed good to excellent levels of potency (IC50 ≤ 6 μM), while being non-hemolytic. N-Phenyl-3-thiocyanato-1H-indole and 1-methyl-2-(4-chlorophenyl)-3-thiocyanato-1H-indole showed good to high potency against all the cell lines. On the other side, the N-(4-chlorophenyl)-, 2-(4-chlorophenyl)- and 2-phenyl- 3-thiocyanato-1H-indole derivatives were slightly less active against the test cell lines. Overall, these results suggest that the indole-3-thiocyanate motif can be suitably decorated to afford highly cytotoxic compounds and that the substituted indole can be employed as a useful scaffold toward more potent compounds., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)