Short communication Novel metronidazoleechalcone conjugates with potential to counter drug resistance in Trichomonas vaginalis Amit Anthwal a, b , U. Chinna Rajesh b , M.S.M. Rawat a, * , Bhavana Kushwaha c , Jagdamba P. Maikhuri c , Vishnu L. Sharma d , Gopal Gupta c , Diwan S. Rawat b, * a Department of Chemistry, H.N.B. Garhwal University (A Central University), Srinagar (Garhwal), Uttarakhand 246174, India b Department of Chemistry, University of Delhi, Delhi 110007, India c Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India d Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India article info Article history: Received 21 December 2013 Received in revised form 24 March 2014 Accepted 27 March 2014 Available online 28 March 2014 Keywords: Trichomonas vaginalis Metronidazole Drug resistance HeLa cell line abstract Trichomoniasis is the most prevalent, curable sexually transmitted disease (STD), which increases risk of viral STDs and HIV. However, drug resistance has been developed by some strains of Trichomonas vag- inalis against Metronidazole (MTZ), the FDA approved drug against trichomoniasis. In the present study twenty two chalcone hybrids of metronidazole have been synthesized in a quest to get new molecules with higher potential against metronidazole-resistant T. vaginalis. All new hybrid molecules were found active against T. vaginalis with varying levels of activity against MTZ-susceptible and resistant strains. Eight compounds (4a, 4c, 4d, 4e, 4f, 4h, 4q and 4s) were found as active as the standard drug with an MIC of 1.56 mg/ml against MTZ-susceptible strain. However, compounds 4e, 4h and 4m were 4-times more active than MTZ against drug-resistant T. vaginalis, amongst which 4e and 4h were most prom- ising against both susceptible and resistant strains. Ó 2014 Published by Elsevier Masson SAS. 1. Introduction Sexually transmitted diseases have long been a big threat to mankind in developing as well as developed countries [1e3]. Nearly 340 million new cases of curable STI’s are reported every year world-wide and in which trichomoniasis is a major contrib- utor. Metronidazole (MTZ) is a drug of choice for trichomoniasis, which is also approved by the US-FDA [4]. However, the situation has been worsened by the resistance developed by microbes against MTZ. The Trichomonas vaginalis infection damages the vaginal epithelium, which increases the risk of women getting infected by HIV and chances of infected women transmitting HIV to her sexual partner(s) are also increased considerably [5,6]. The Concept of hybrid molecules is a rational approach to overcome the problem of drug resistance by introducing a new pharmacophore in a biologically active molecule to get new molecule of therapeutic importance [7,8]. In a quest to synthesize new hybrid molecules with better anti-trichomonas activity, especially against the resis- tant strain, we planned to modify the metronidazole framework at hydroxyl group. The rationale for selecting hydroxyl group was that due to its presence MTZ metabolizes into 1-acetic acid metabolite, which results in loss of activity [9]. Many research groups have attempted to modify MTZ at hydroxyl group in order to get a molecule with enhanced activity against T. vaginalis [10e14]. The chalcone is another widely studied pharmacophore with wide range of biological activities. The chalcones exhibit anticancer [15,16], anti-inflammatory [17,18], anti-oxidant [19,20] and anti- microbial [21] activities. As a part of our ongoing research towards development of biologically important molecules, we designed novel metronidazoleechalcone conjugates and anticipated that if such an active pharmacophore is attached to metronidazole the resulting hybrid molecules are likely to be more active especially against MTZ-resistant Trichomonas., we herein report synthesis and anti-trichomonas activity of 22 novel metronidazoleechalcone conjugates. The structure of MTZ was modified at hydroxyl group to attach chalcone moiety by covalent bond (Fig. 1 , Scheme 1). The compounds (4ae4v) were synthesized by varying substituents on aromatic ring of chalcone moiety; these compounds were screened for anti-trichomonas activity against susceptible and resistant strains of T. vaginalis. The safety of the most promising molecules was evaluated against human cervical (HeLa) cell line. * Corresponding authors. E-mail addresses: msmrawat@gmail.com (M.S.M. Rawat), dsrawat@chemistry. du.ac.in (D.S. Rawat). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.03.076 0223-5234/Ó 2014 Published by Elsevier Masson SAS. European Journal of Medicinal Chemistry 79 (2014) 89e94