New Inhibitors of indoleamine 2,3-dioxygenase 1: molecular modelling studies, synthesis and biological evaluation

Indoleamine 2,3-dioxygenase 1 (IDO1) is a monomeric heme-containing enzyme that catalyzes the rate limiting step of the L-tryptophan catabolism via the kynurenine pathway. Recent evidences suggested that IDO1 inhibition is an attractive target for anticancer therapy.1,2 The effort in the development of IDO1 inhibitors led to the discovery of several chemical entities. However, only a small number of molecules reached the clinical status. Herein, we report a virtual screening study, which led to the identification of compound 1 as a new IDO1 inhibitor. In order to improve the biological activity of this new class of IDO1 inhibitors, indoles 2-26 were designed, synthesized and tested. Among these, derivative 17 exhibited an IC50 value of 7 microM, being the most active compound of the series. Structure-activity relationship studies pointed out that: (a) sulphur bridge was crucial, resulting its oxidation to sulphone or substitution with ketone or methylene groups detrimental to enzyme inhibition; (b) substitution of the indole nucleus with halogen atoms was allowed only at positions 4-6, proving 5-Cl as the best one and (c) introduction of 3,5-(OMe)2 substitution pattern on the phenyl ring gave the most promising compound. Furthermore, compounds 1 and 17 induced a dose-dependent growth inhibition in IDO1 expressing HTC116 and HT29 cancer cell lines. 3-D QSAR studies were carried out in order to rationalize obtained results and suggest new chemical modifications. References [1] Röhrig, U. F.; Majjigapu, S. R.; Vogel, P.; Zoete, V.; Michielin, O. Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors. J. Med. Chem. 2015, 58, 9421−9437. [2] Dounay A. B.; Tuttle, J. B.; Verhoest, P. R. Challenges and Opportunities in the Discovery of New Therapeutics Targeting the Kynurenine Pathway. J. Med. Chem. 2015, 58, 8762−8782.