Novel Cyano- and Amidinobenzothiazole Derivatives: Synthesis, Antitumor Evaluation, and X-ray and Quantitative Structure−Activity Relationship (QSAR) Analysis

Abstract

Synthesis of a series of novel cyano- and amidinobenzothiazole derivatives 3-31 is described. All studied amidino derivatives showed noticeable antiproliferative effect on several tumor cell lines. Cyano derivatives 11-17 showed considerably less pronounced activity because of their poor solubility in aqueous cell culture medium, which was confirmed by the principal components (PC) analysis. Compounds 21, 22, 28, and 29 were tested for their effects on the cell cycle and apoptosis, whereby 22 and 29, having methyl group at the C-6 position in pyridine ring, showed drastic cell cycle perturbations that were both concentration- and time-dependent and induced apoptosis. The QSAR modeling, based on the physicochemical descriptors and on the measured biological activities, indicated the relevance of molecular polarizability and particular distribution of pharmacophores on the molecular surface for activity. In conclusion, benzothiazoles containing either isopropylamidino or imidazolyl groups will be considered as starting compounds for further investigation on lead identification.

Design, Synthesis and Anticancer Screening of Novel Pyrazole Derivatives Linking to Benzimidazole, Benzoxazole and Benzothiazole

“…Solvent system was chloroform: methanol (in different ratio). 1 H NMR spectra were determined in DMSO-d 6 solvent with Varian Gemini 300 MHZ Spectrometer. Peak positions were given in parts per million (δ) downfield the tetramethylsilane as internal standard.…”

“…Cancer still remains a mean threat to human health, representing the second leading cause of death worldwide [1]. It is estimated that 13.1 million people will die from cancer in 2030 [2].…”

“…It is estimated that 13.1 million people will die from cancer in 2030 [2]. Recently, 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 [1]. In this context, the major challenge is the development of more effective and safe drugs for the treatment of cancer.…”

“…In this context, the major challenge is the development of more effective and safe drugs for the treatment of cancer. Through searching in the literature, it was found that benzothiazole derivatives play an important role on designing of new drugs, since they present an interesting pharmacological profile [3], including anti-allergic [4], anti-inflammatory [5], antitumor [6], analgesic [7], antimicrobial [8,9], anthelmintic [10], antileishmanial [11], anticonvulsant [12] activities, also with considerable efficacy as kinase, topoisomerase I/II and transretinoic acid metabolism inhibitors [1]. In addition, pyrazole nucleus is an important pharmacophore with a wide range of therapeutically activities such as antitumor [13], antibacterial, anti-inflammatory [14] and hypotensive [14] efficacies and also acts as ligands for benzodiazepine receptors [15].…”

New spiroindolinones bearing 5-chlorobenzothiazole moiety

“…Sunitinib malate (SU11248) (X), the first oral drug acting as a multitarget tyrosine kinases inhibitor, has been approved for the treatment of gastrointestinal stromal tumors, renal cell carcinoma and several authors recall how the combination of SU11248 represent a promising novel treatment strategy against tumors (Figure 1) 17 . Benzothiazole derivatives are highly selective and potent antitumor agents [18][19][20][21][22] . Analysis of their structure-activity relationships shows that most of these compounds possess a second aromatic ring linked directly to the 2-position of benzothiazole ring or through an amine, an amide or an urea moiety.…”