RESEARCH COMMUNICATIONS CURRENT SCIENCE, VOL. 115, NO. 12, 25 DECEMBER 2018 2287 *For correspondence. (e-mail: chowrasia.deepak@gmail.com) Synthetic modulation including structure establishment, antiproliferative activity of some p-aryl substituted (Z)-2-cyano- ethylideneacetohydrazides, and their structure activity relationship Deepak Chowrasia 1,3, *, Nisha Sharma 1 , Ajay Kumar 1 , Md Arshad 2 , Sahabjada Siddiqui 2,4 , Asif Jafri 2 and Juhi Rahis 2 1 University Institute of Pharmacy, Chhatrapati Shahu ji Maharaj (CSJM) University, Kalyanpur, Kanpur 208 024, India 2 Department of Zoology, Lucknow University, Lucknow 226 007, India 3 School of Pharmaceutical Sciences, Rajiv Gandhi Technical University, Airport Bypass Road, Gandhi Nagar, Bhopal 462 036, India 4 Department of Biotechnology, ERA’s Lucknow Medical College and Hospital, Era University, Lucknow 226 003, India A series of p-substituted aryl-2-cyanoethylidene- acetohydrazides derivatives (2a-j) were successfully synthesized in the laboratory (yield 60–80%). The synthesized compounds were screened for their anti- proliferative activity against MCF-7 (estrogen dependent human breast cancer cell line), SaOS-2 (osteosarcoma cell line), and K562 (myeloid leukemia cell line) by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) reduction assay. They showed moderate to mild antiproliferative activity, (2j) being the most potent in the series with an IC 50 55, 64 and 35 μM against MCF-7, SaOS-2 and K562 cell lines, depict p-nitro as a better antiproliferative sub- stituent comparatively. We have also tested the hypo- thesis – ‘Electron withdrawing phenomenon affects antiproliferative activity’. Keywords: Cancer, cyanoacetohydrazide, electron with- drawing ring substituent, MTT assay. CANCER is the second leading cause of mortality respon- sible for 8.8 million deaths (2015). WHO estimates around 9.6 million deaths in 2018 (ref. 1). Being genomic in origin and having direct impact on cellular prolifera- tion as well as differentiation machinery, cancer in earlier and/or in-later stages causes mass-lumps, exposing living tissue to an unnecessary metabolic burden rendering them to perform normal physiological task 2,3 . Though global cancer research has come a long way, the need for novel anticancer agent/s is still unfulfilled and is the need of the present era. Rapid progression of the disease, higher inci- dence rate, and uncontrolled mortality have alarmed researchers worldwide to search for better cancer chemo- therapeutics. However, excessive distal metastasis, multi- organ involvement, delayed detection, uneconomical and longer treatment plan, drug resistance, therapeutic side effects are some protuberants rendering for its cure and management. Other facets such as severe side-effects of cancer regime promote poor patient compliance leading to progression of the disease and causing death. In the past few years, heterocyclic 4–8 and non-heterocyclic moieties, especially nitrogen containing motifs endowed with anti-proliferative activity, were extensively targeted, among which hydrazide-hydrazone including their struc- turally modified derivatives were proved to be prominent, versatile, and potent core template for development of novel anticancer agent/s 9–16 . Hydrazones (R 1 R 2 C=NNH 2 ) are related aldehyde or ketone derivatives in which oxygen is replaced covalently with –NNH 2 functionality consecrating the core structure with two active centres (viz. carbon and nitrogen) respon- sible for wide biological activities. Likewise, hydrazide (E(O=)–NR–NR; R=H), the acylated derivative of hydra- zine, is another distinct class possessing covalently bonded dual nitrogen system configured for formation of nitrogen assisted inter-chemical bonds with host-targeted protein conferring the molecule diversified pharmacolog- ical activities 17–20 . 2-Cyano-N′-(1-(pyridine-3-yl)ethylidene)acetohydazide was selected as lead molecule for derivatization and yield newer synthetic daughter molecules. The main criteria that were considered while selecting this molecule in- clude ease of laboratory derivatization for structure activ- ity relationship (SAR) development, availability of synthetic building block, fewer level reaction, handling procedure, product purity including yield (60–80%), optimum molecular weight (less than 300) of end prod- uct, Lipinski rule of five, novelty of chemical structure, and in vitro reported sub-micromolar activity of lead template against estrogen dependent breast cancer cell line (MCF-7) 21 . All commercial chemicals and solvents used are rea- gent grade and were used without further treatment unless otherwise noted. 1 H-NMR spectra were recorded by Bruker Avance-II NMR spectrometer. Chemical shift was recorded in parts per million (ppm) and reported relative to the TMS. Mass spectra were recorded on an applied Biosystem Qtrap 3200 LC-MS/MS system in ESI mode. The FT-IR spectra of the synthesized compounds were recorded on Brukers FTIR. Melting points of all com- pounds were determined using Veego digital melting point apparatus and reported uncorrected. The purity of compounds was confirmed by thin layer chromatography (TLC) using Merck silica gel 60-F 254 coated alumina plates both at near and far UV. Synthesis of ethylcyanoacetyl hydrazide (1a) (Scheme 1) 22 : A mixture of ethyl cyanoacetate (1 M) and hydra- zine hydrate (1 M) in ethanol (5 ml) was stirred at 0°C until reddish brown mass of cynoacetylhydrazine was