Molecular Diversity https://doi.org/10.1007/s11030-018-9865-9 ORIGINAL ARTICLE Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents Eman A. Fayed 1 · Sally I. Eissa 2,3 · Ashraf H. Bayoumi 4 · Nirvana A. Gohar 1 · Ahmed B. M. Mehany 5 · Yousry A. Ammar 6 Received: 5 March 2018 / Accepted: 2 August 2018 © Springer Nature Switzerland AG 2018 Abstract 3,5-Diamino-4-(3-trifluoromethylphenyldiazenyl)-1H -pyrazole was used as a starting scaffold for the synthesis of new pyrazole-based heterocycles to study their effects on the proliferation of three human cancer cell lines; human liver car- cinoma cell line (HepG-2), colon cancer cell line (HCT-116) and human breast cancer cell line (MCF-7) using MTT assay. The synthesized compounds were characterized on the basis of IR, 1 H NMR, 13 C NMR, mass spectral data and elemental analysis results. Cytotoxicity assay results revealed that some of the compounds showed potent growth inhibition against all the cell lines tested, with IC50 values in the range of 0.64–7.73 μg/mL. Breast cancer cells were used for further detailed studies to understand the mechanism of cell growth inhibition and apoptosis-inducing effect of the most active compounds. The results indicated that compounds 3a, 10b and 11a arrested MCF-7 cells at G2/M phase of the cell cycle and might induce apoptosis via caspase-3-dependent pathway. Molecular modeling and binding mode analysis of the most active compounds to caspase 3 active site further provide a synergistic mechanism for their pro-apoptotic effects. In order to explore the structural requirements controlling the observed cytotoxic properties, 3D pharmacophore model was generated. Keywords Synthesis · Pyrazole · Pyrazolo[1,5-a]pyrimidines · Anti-proliferative activity · Apoptosis Introduction Cancer is considered a large group of diseases character- ized by uncontrolled, rapid and pathological proliferation of abnormally transformed cells. Despite recent advances in cancer therapy, cancer is still the second leading cause B Sally I. Eissa sarazizo2005@yahoo.com 1 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University (Girls), Cairo, Egypt 3 Faculty of Pharmacy, Al-Maarefa University for Science and Technology, Riyadh, Kingdom of Saudi Arabia 4 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt 5 Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt 6 Organic Chemistry Department, Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt of death after cardiovascular disorders throughout the world [1]. Resistance to chemotherapeutic agents remains a key challenge in the fight against cancer. Another challenge for chemotherapy is lack of selectivity. Generally anticancer drugs destroy normal cells as well as cancer cells and often cause serious adverse effects. Many efforts have been made to develop safe and effective ways of treating this disease and to search for novel chemotherapeutic agents with minimal side effects [2]. Apoptosis is the programmed cell death which maintains the healthy survival/death balance in normal cells. Disrup- tion or inappropriate regulation of the process of apoptosis results in several diseases including cancer. The unique char- acteristics of apoptosis are the activation of various enzymes that are cysteine protease families called caspases. Caspase 3 is considered the key protein of the caspase family, which are highly conserved in multicellular organisms and function as central regulators of apoptosis. Thus, targeting critical reg- ulators of apoptosis with the goal of inducing apoptosis in cancer cells has emerged as an attractive strategy in cancer therapy [3–5]. 123