One-pot synthesis and anticancer studies of 2-arylamino-5-aryl-1,3,4- thiadiazoles Dalip Kumar a,⇑ , Buchi Reddy Vaddula a , Kuei-Hua Chang b , Kavita Shah b,⇑ a Department of Chemistry, Birla Institute of Technology and Science, Pilani 333031, Rajasthan, India b Department of Chemistry and Purdue Cancer Center, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA article info Article history: Received 11 December 2010 Revised 22 February 2011 Accepted 23 February 2011 Available online 26 February 2011 Keywords: 1,3,4-Thidiazoles Anticancer agents One-pot synthesis Cancer cell lines Oxidative cyclization abstract A series of 2-arylamino-5-aryl-1,3,4-thiadiazoles 1a–j were synthesized and screened for their anticancer activity against various human cancer cell lines. The novel one-pot synthesis of 1,3,4-thiadiazoles was achieved by refluxing aryl aldehydes, hydrazine hydrate, and aryl isothiocyanates in methanol followed by oxidative cyclization with ferric ammonium sulfate. The compounds 1g–j with trimethoxyphenyl at the C-5 position displayed extremely potent anticancer activity with at least twofold selectivity (IC 50 : 4.3–9.2 lM). The nature of substituent on the C-2 arylamino ring may be critical in opting for the selec- tivity towards a particular cancer cell. Ó 2011 Elsevier Ltd. All rights reserved. 1,3,4-Thiadiazoles are five-membered ring systems that have gained prominence by exhibiting a wide variety of biological activ- ities as well as producing useful intermediates in several organic preparations. 1–7 They have interesting pharmacophores that dis- play a broad spectrum biological activity. The lower toxicity and in vivo stability of thiadiazole nucleus is attributed to its aromatic- ity. 8 Thiadiazoles have exhibited potential antiglaucoma, 9 antiin- flammatory, 1 antitumor, 7 antiulcer, 10 antibacterial, 11 antiviral, 12 analgesic, 13 antiepileptic, 5 antifungal, 11 and radioprotective activities. 14 The marketed drugs, acetazolamide, methazolamide, globucid, etc. showcase their therapeutic potential. Thiadiazoles, bioisosters of thiazoles and oxadiazoles, are known to have interesting electro-optical properties 15 and also act as corrosion and oxidation inhibitors, 16 complexation reagents for dyes and metal ions. 17–20 The 1,3,4-thiadiazoles, their isomeric forms and bioisosters are extensively investigated for their anticancer activity due to their therapeutic potential. 7,21–23 In this direction, our research group has successfully explored various heterocycles to develop a potential anticancer compound. 24–27 2-Amino-1,3,4-thiadiazole, 2-ethylamino-1,3,4-thiadiazole, 2,2 0 -(methylenediamino)bis-1,3, 4-thiadiazole and their N-substituted derivatives were found to exhibit very good anticancer activity but suffered from adverse side-effects. 28–30 2-(4-Fluorophenylamino)-5-(2,4-dihydroxy-phe- nyl)-1,3,4-thiadiazole (FABT), a promising anticancer compound for treating malign tumors of the nervous system, inhibits prolifer- ation by decreasing cell division and inhibiting metastasis. 22,31 It was shown that the one of the important structural unit in several known natural antimitotic agents such as Combretastatin A-4, Colchicine, Podophyllotoxin, and Steganacin, which bind at the Colchicine site on tubulin, is a trimethoxyaryl moiety (Fig. 1). 32,33 The incorporation of crucial structural features of anticancer com- pounds (3,4,5-trimethoxyphenyl and 4-hydroxy-3-methoxyphenyl moieties) into 1,3,4-thiadiazoles may lead to a potent anticancer compound (Fig. 1). Generally, preparation of 1,3,4-thiadiazoles involve use of diacylhydrazide precursors under different reaction conditions. Symmetrical 2,5-disubstituted-1,3,4-thiadiazoles are prepared by condensation of aryl aldehydes, hydrazine, and sulfur in ethanol under microwave irradiation. 34 The general routes for the prepara- tion of various 1,3,4-thiadiazoles involve either synthesis of acyl thiohydrazides and then cyclization or thionation of acyl hydrazides followed by oxidative cyclization of thiosemicarba- zones. Gierczyk and Zalas reported the four step synthesis of 2,5-disubstituted-1,3,4-thiadiazoles from pentafluorophenyl esters. 35 Also a robust protocol for the solid phase synthesis of 5-alkyl/aryl-2-alkylamino-1,3,4-thiadiazoles was described from resin bound thiosemicarbazide. 36 Oruc et al., prepared 1,3,4-thi- adiazoles in four steps utilizing acyl halides and aryl isothiocya- nates. 37 The 1,3,4-thiadiazoles were also achieved in good yields from the reaction of 1,3,4-oxadiazoles with thiourea. 38 Recently reported one-pot convenient synthesis of 1,3,4-thiadiazoles by 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.02.083 ⇑ Corresponding authors. Tel.: +91 1596 245073 279; fax: +91 1596 244183 (D.K.); tel.: +1 765 496 9470 (K.S.). E-mail addresses: dalipk@bits-pilani.ac.in (D. Kumar), shah23@purdue.edu (K. Shah). Bioorganic & Medicinal Chemistry Letters 21 (2011) 2320–2323 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl