Preliminary communication Novel terpene based 1,4,2-dioxazoles: Synthesis, characterization, molecular properties and screening against Entamoeba histolytica Mohmmad Younus Wani a , Fareeda Athar a, *** , Attar Salauddin b , Subhash Mohan Agarwal c , Amir Azam b , Inho Choi d, ** , Abdul Roouf Bhat d, * a Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India b Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India c Bioinformatics Division, Institute of Cytology and Preventive Oncology, Noida 201301, India d School of Biotechnology, Yeungnam University, 241-1, Dae-Dong, Gyeongsan 712749, South Korea article info Article history: Received 26 April 2011 Received in revised form 29 May 2011 Accepted 7 June 2011 Available online 14 June 2011 Keywords: Dioxazole Terpene Anti-amoebic activity Cytotoxicity studies abstract In present investigation a series of 20 dioxazole analogues (1e20) were synthesized, characterized and subjected to molecular properties prediction, anti-amoebic screening and cytotoxicity evaluation. Out of the twenty compounds viz. 3,5-substituted-1,4,2-dioxazoles, six compounds have shown IC 50 values in the range (1.00e1.10 mM) lower than the standard drug metronidazole (IC 50 ¼ 1.45 mM). The toxicological studies of the active compounds on H9c2 rat cardiac myoblasts showed that all compounds were nontoxic. The pKa, and log P values have also been predicted. Compound 8 showed the most promising results based on anti-amoebic evaluation, cytotoxicity studies and physico-chemical properties prediction. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction Amoebiasis, an infectious disease caused by Entamoeba histo- lytica, results in severe liver and brain abscess and causes high rate of morbidity and mortality in humans. Metronidazole, the 5-nitroimidazole drug has been the drug of choice for several decades in the treatment of amoebiasis [1]. However, there are concerns regarding its carcinogenicity [2] and recent studies have reported several toxic effects such as genotoxicity, gastric mucus irritation, and spermatozoid damage [3,4]. Furthermore, there are occasional reports of failure with metronidazole suggesting that this could probably be heralding the development of drug resis- tance clinically [5]. Recurrence of amoebic liver abscess even after treatment with metronidazole has been reported and parasites may survive in spite of adequate treatment [6]. Terpenoids are natural molecules with antimicrobial, antifungal, antiparasitic, antiviral, antiallergenic, antispasmodic, antihyperglycemic, antiin- flammatory, chemotherapeutic and immunomodulatory properties [7e18]. The versatile biological applications of azoles made it a targeted investigatory class of compound [19]. Counting the antiparasitic properties of terpenes [20e22] and anti-amoebic properties of 1,4,2-dioxazoles [23e25], we proposed the synthesis of terpene based 1,4,2-dioxazoles. In the development of drugs intended for oral use, good drug absorption and appropriate drug delivery are very important [26]. About 30% of oral drugs fail in development due to poor phar- macokinetics [27]. Among the pharmacokinetic properties, a low and highly variable bioavailability is indeed the main reason for stopping further development of the drug [28]. Moreover, the knowledge of ionization constant is an important challenge for understanding various phenomena like biological uptake, phar- macological activity or in vivo studies. Hence, the discovery of new molecules require accurate determination of pKa and log P values. In the present research work some new terpene-based dioxazole derivatives 1e20 have been synthesized, screened for anti- amoebic activity and cell cytotoxicity. Their pKa and log P values have been determined in order to understand the chemical interactions between the compound of interest and its pharma- cological target. * Corresponding author. Tel.: þ82 53 810 3589; fax: þ82 53 810 4769. ** Corresponding author. Tel.: þ82 53 810 3024; fax: þ82 53 810 4769. *** Corresponding author. Tel.: þ91 11 26981717x4492; fax: þ91 11 26980164. E-mail addresses: fareeda.cirbs@jmi.ac.in (F. Athar), inhochoi@ynu.ac.kr (I. Choi), abroouf@gmail.com (A. Roouf Bhat). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2011.06.005 European Journal of Medicinal Chemistry 46 (2011) 4742e4752