Development of a series of 5-substituted 6-fluoro indole derivatives and evaluation of their biological activity

This study focused on the development of a quantitative structure activity relationship (QSAR) model to predict the cystic fibrosis transmembrane conductance regulator (CFTR) binding activity of a series of 5-substituted 6-fluoro indole derivatives, structures similar to the Tezacaftor molecule, an approved CFTR modulator drug. Also, synthetic routes for the preparation of these molecules were explored and their antiproliferative activity, due to the potential link between CFTR and cancer, was also aimed to be assessed. A predictive QSAR model has been developed using regression-based learning techniques as Kernel-based Partial Least Squares regression (KPLS), providing satisfying statistical results as R2=0.8865, Q2= 0.7142, and RMSE (root mean square error) = 0.3985. Promising pEC50 values were predicted from the developed model since the obtained values were found to be between 4.79 and 5.11 for the all of the fifteen tested 5-substituted 6-fluoro indole derivatives. To achieve the synthesis of these molecules various sulfonyl chlorides, aldehydes, isocyanates, and isothiocyanates were coupled with 2‐[1‐(benzyloxy) ‐2‐methylpropan‐2‐yl] ‐6‐fluoro‐1H‐indole‐5‐amine. Yet only some sulfonamide structures were isolated purely. The structures of synthesized compounds were elucidated using 1H-NMR, 13C APT-NMR, COSY-NMR, HSQC-NMR, and HPLC-UV-MS techniques. Finally, the synthesized compounds were tested for their in vitro anticancer activity. Their cytotoxicity was evaluated using the NCI-Sulforhodamine B assay on ovarian OVSAHO and OVCAR-3 cancer cell lines. None of the synthesized 5-substituted 6-fluoro indole derivatives was found to exhibit notable cytotoxicity. Keywords: QSAR, cystic fibrosis, CFTR modulators, cancer, indole, tezacaftor