Design and synthesis of some thieno[2,3- c ]pyridazine derivatives of expected anticancer activity
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Med Chem Res (2013) 22:2589–2601 DOI 10.1007/s00044-012-0258-9
ORIGINAL RESEARCH
Design and synthesis of some thieno[2,3-c]pyridazine derivatives of expected anticancer activity Afaf K. El-Ansary • Aliaa M. Kamal Mokhtar AbdHafiz Al-Ghorafi
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Received: 22 February 2012 / Accepted: 21 September 2012 / Published online: 4 October 2012 Ó Springer Science+Business Media New York 2012
Abstract Design and synthesis of some new thienopyridazine derivatives as anticancer agents were the goal of this work. Accordingly, a series of novel compounds were synthesized via reacting thienopyridazine carboxylic acid hydrazide with different organic reagents. Twelve novel compounds were selected by National Cancer Institute for a full anticancer screening assay where seven of the investigated compounds showed non-selective broad spectrum and promising activity almost against all cancer cell lines. One of the most active compounds was chosen to be evaluated against 60-cell line panel at five concentration levels and revealed a remarkable growth inhibition activity. Keywords Antitumour agents Thieno[2,3-c]pyridazines Cytotoxic activity Pharmacophores Improving chemotherapy regimen
Introduction During the last four decades, intensive research have been conducted on pyridazine chemistry because many derivatives were found to have a wide variety of biological activities, e.g. psychomimetic (Wermuth et al., 1989), anti inflammatory (Tewari and Mishra, 2001; Takaya et al., 1979), analgesics (Rohet et al., 1997), anticonvulsant (Moreau et al., 1994), antiasthmatic and bronchodilator (Yamaguchi et al., 1995), antihypertensive (Pifferi et al., 1975; Tomil et al., 1998; McEvoy and Allen, 1974; Curran and Ross, 1974), phosphodiesterase IV inhibitors (Piaz et A. K. El-Ansary A. M. Kamal (&) M. A. Al-Ghorafi Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11561, Egypt e-mail: [email protected]; [email protected]
al., 1997; Pieretti et al., 2006), antimicrobial (Hassall et al., 1979; Radwan and Bakhite, 1999; Kandile et al., 2009; Deeb et al., 2004; Nagawade et al., 2005; Akbas and Beber, 2005; Wu et al., 2009), antidiabetic (Mylari et al., 2005; Rathish et al., 2009), positive inotropic activity(Mertens et al., 1990; Combs et al., 1992), antianxiety (Lewis et al., 2006) and antitumour activity (Malinka and Redzicka, 2004; Byth et al., 2004; Brana et al., 2005; Shenvei et al., 2005). Likewise fused pyridazines, e.g. imidazopyridazines were designed as potent selective CDK2 inhibitors and provided useful leads for discovery and development of CDK inhibitors (Byth et al., 2004). Pyrazolopyridazines and their analogues were identified in a high-throughput screening as potent inhibitor of CDK1/ cyclin B and have selectivity for the CDK family (Brana et al., 2005). Moreover, thieno[2,3-d]pyridazines were prepared and found to have I.Kappa.B kinase (IKKs) inhibitors that are useful as anticancer (Shenvei et al., 2005). Thieno[2,3-c]pyridazines bearing several pharmacophores that hopin
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