Original article Synthesis and antitumor evaluation of some new 1,3,4-oxadiazole-based heterocycles Samir Bondock a, b, * , Shymaa Adel a , Hassan A. Etman a , Farid A. Badria c a Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt b Department of Chemistry, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia c Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, ET-35516 Mansoura, Egypt article info Article history: Received 17 October 2011 Received in revised form 2 December 2011 Accepted 7 December 2011 Available online 13 December 2011 Keywords: 1,3,4-Oxadiazole Pyrazole Thiazole Thiophene Antitumor activity abstract The synthetic strategies and characterization of some novel 1,3,4-oxadiazole derivatives carrying different pharmacophores and heterocyclic rings that are relevant to potential antitumor and cytotoxic activities are described. The antitumor activities of the newly synthesized compounds were evaluated according to the protocol of the National Cancer Institute (NCI) in-vitro disease-oriented human cells screening panel assay. The results revealed that five compounds, namely 2, 7a, 11a, 12b, and 17; displayed promising in-vitro antitumor activity in the 4-cell lines assay. Incorporating a thiazole ring to 1,3,4- oxadiazole skeleton resulted in better antitumor activities than those displayed by the pyrazole and thiophene ring systems. Transformation of 1,3,4-oxadiazole 2 to N-(6-amino-7H-pyrazolo[5,1-c][1,2,4] triazol-3-yl)benzamide (15) diminished the antitumor activity. Ó 2011 Elsevier Masson SAS. All rights reserved. 1. Introduction 1,3,4-Oxadiazoles are an important class of heterocyclic compounds with a wide range of biological activities such as anti- viral [1], antimicrobial [2], antineoplastic [3], fungicidal [4], anti- cancer [5e8], inhibition of tyrosinase [9] and cathepsin K [10]. They are also useful intermediates in organic synthesis [11] and widely employed as electron transporting and hole-blocking materials [12]. Further, 1,3,4-oxadiazole heterocycles are very good bioisosteres of amides and esters, which can contribute substantially in increasing pharmacological activity by participating in hydrogen bonding interactions with the receptors [13]. 2,4-Disubstituted 1,3,4- oxadiazoles have also attracted significant interest because of their applications in organic light-emitting diodes, photoluminescence, polymers, and material science [14,15]. In view of the great medicinal significance and material applications a number of synthetic routes have been developed for 1,3,4-oxadiazole. The majority of them are based on the cyclization of the diacylhydrazides or acylth- iosemicarbazides and the oxidation of acylhydrazones [16] with a variety of reagents such as thionyl chloride, phosphorus oxy- chloride, or sulfuric acid, usually under harsh reaction conditions. Cancer treatment has been a major endeavor of research and development in academia and pharmaceutical industry for the last many years as it is one of the leading causes of death [17]. Many of the available anticancer agents exhibit undesirable side effects such as reduced bioavailability, toxicity and drug-resistance [18e22]. Therefore, the search for novel and selective anticancer agents is urgently required due to problems associated with currently available anticancer drugs. Encouraged by the afore-mentioned findings and in a continua- tion of an ongoing program aiming at finding new structural leads with potential chemotherapeutic activities [23e30]; it was ratio- nalized to synthesize some novel 1,3,4-oxadiazoles-substituted heterocycles that would produce anticancer activity. The proposed candidates were supported with a variety of pharmacophoric groups which would impart various electronic and lipophilic properties. Synthesis of 1,3,4-oxadiazoles with an amide group was rationalized on the fact that many antitumor antibiotics such as bleomycin, and pyrazofurin incorporate in their structures amidic group [31]. 2. Results and discussion 2.1. Chemistry The suggested synthetic plans to obtain the target compounds are shown in Schemes 1 and 2. The versatile hitherto unreported * Corresponding author. Department of Chemistry, Faculty of Science, Mansoura University, El-gomhuria street, ET-35516 Mansoura, Egypt. Tel.: þ20 502369267; fax: þ20 502246781. E-mail address: Bondock@mans.edu.eg (S. Bondock). Contents lists available at SciVerse 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.2011.12.013 European Journal of Medicinal Chemistry 48 (2012) 192e199