1 Scientific RepoRts | 6:23401 | DOI: 10.1038/srep23401 www.nature.com/scientificreports one-pot synthesis and in-vitro anticancer evaluation of 5-(2′-indolyl)thiazoles Buchi Reddy Vaddula 1 , Mukund p. tantak 2 , Rachana sadana 3 , Michael A. Gonzalez 1 & Dalip Kumar 2 A series of 5-(2′-indolyl)thiazoles were synthesized and evaluated for their cytotoxicity against selected human cancer cell lines. The reaction of thioamides 3 with 3-tosyloxypentane-2,4-dione 4 led to in situ formation of 5-acetylthiazole 5 which upon treatment with arylhydrazines 6 in polyphosphoric acid resulted in the formation of 5-(2′-indolyl)thiazoles 2. Among the synthesized 5-(2′-indolyl)thiazoles, compounds 2d–f, and 2h exhibited encouraging anticancer activity and also selectivity towards particular cell lines (IC 50 = 10–30 μM). Further studies on the SAR of compound 2e may result in good anticancer activity. Multicomponent reactions (MCRs) are one-pot multi-step reactions comprising three or more substrates. Tey are popular in drug discovery for being important tools in rapidly generating a library of novel compounds with diverse substitutions and molecular complexity 1 . Te advantages associated with MCRs include atom economy, simple operation, and high yields of the products along with eliminating the need for isolation of intermediates. Additionally, the application of microwaves in organic synthesis has enabled the chemists to accelerate reactions, improve yields, and easily achieve desired products 2–4 . Indole alkaloids extracted from plants and marine sources are well known for their chemistry and biology. Te biological signifcance of these naturally available alkaloids secured much attention resulting in exploring the structural novelty of these molecules. 5-(2 ′ -Indolyl)azoles 2 possess an indole ring at the C-5 position of azole ring as in 5-(3 ′ -indolyl)azoles 1, but is connected at the second position of indole unlike the third position in natural derivatives (Fig. 1). Tiazole derivatives are one of the most revered compounds with many applications and biological activi- ties attributed to them. Indolylthiazole and its related heterocyclic systems are found in many natural products. Te anticancer compounds, Camalexin 5,6 and the naturally occurring BE 10988, are thiazole-substituted indole derivatives 7 . Additionally, the thiazole and benzothiazole derivatives of indole have been found to exhibit broad therapeutic activities including antimicrobial and antitumor 8–15 . Te naturally occurring bis(indolyl) alkaloids and their analogues, in general, have also exhibited signif- cant anticancer activities 16 . For example, Nortopsentins and Topsentins represent a class of deep-sea sponge metabolites which display potent biological activities such as antitumor 17 , antiviral 18 , and antiinfammation 19 . Nortopsentin analogues, such as 2,4-bis(indolyl)thiazoles, also have exhibited good cytotoxicity against a panel of human tumor cell lines with GI 50 values as low as 0.888 μM 13 . Te closely related thiazolylbenzofuran derivatives 20 have been shown to possess leukotriene and SRS-A antagonist or inhibitor activities. Our research group has pre- pared a series of indolylazoles such as 5-(3-indolyl)-1,3,4-oxadiazoles 21 , 4-(3-indolyl)oxazoles 22 , 5-(3-indolyl)-1, 3,4-thiadiazoles 23 , and indolyl-1,2,4-triazoles 24 as potential anticancer agents against human cancer cell lines. Instigated by the role of indolylthiazoles and their bioisosteres in a variety of therapeutic activities as well as paucity of their one-pot preparation, we have contrived the synthesis of 5-(2′ -indolyl)-2-substituted thiazoles 2 (Fig. 2). Tis one-pot synthesis was carried out by in situ generation of 5-acetylthiazole 5 from the reaction of thioamide 3 with 3-tosyloxypentane-2,4-dione 4 in ethanol with subsequent treatment of 5 with arylhydrazines 6 in polyphosphoric acid (PPA). 1 Sustainable technology Division, national Risk Management Research Laboratory, U.S. environmental Protection Agency, 26 West Martin Luther King Drive, MS 483, Cincinnati, OH 45268, USA. 2 Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, India. 3 Department of Natural Sciences, University of Houston – Downtown, Houston, TX 77002, USA. Correspondence and requests for materials should be addressed to D.K. (email: dalipk@pilani.bits-pilani.ac.in) Received: 26 June 2015 accepted: 08 October 2015 Published: 29 March 2016 opeN