Diethyl 4-(6-Chloroimidazo[2,1-b]thiazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and Ethyl 4-(6-Chloroimidazo[2,1-b]thiazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Diethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine- 3,5-dicarboxylate and ethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate were obtained simultaneously by the Biginelli reaction using a green protocol and curtailing reaction time

Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100–200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also tested in vivo in the murine BL6-B16 melanoma and E0771 breast cancer cells, causing in both cases a significant reduction in tumor volume

Recent Patents on Thiazole Derivatives Endowed with Antitumor Activity

Cancer is a disease of remarkable importance in the world today and is projected to become the primary cause of death within the coming years, therefore the design and development of new antitumor agents is one of the most pressing research areas in medicinal chemistry. Considering the importance of thiazole ring as scaffold present in a wide range of therapeutic agents, the medicinal chemists have been encouraged to synthesize a large number of novel antitumors bearing this heterocycle, which furnish extensive synthetic possibilities due to the presence of several reaction sites. The present review describes the patents from 2008 to present concerning new thiazole compounds useful for the development of new drug molecules. It has been divided according to the molecular target and describes the pathways involved in the biological activities and the structure of the most potent compounds, together with the screening results

2-Indolinone a versatile scaffold for treatment of cancer: A patent review (2008-2014)

2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block. Areas covered: The present review gives an account of the recent patent literature (2008\u20132014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed. Expert opinion: 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2- indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research

A Patent Review on Thiazole Derivatives (2008-2013)

Thiazole is a well known five membered heterocyclic compound. Various methods have been worked out for its synthesis. In the last few decades, a lot of work has been done on thiazole ring to synthetize derivatives directed to a plethora of molecular targets in order to discover new drug leads. The present review gives an account of the therapeutic patent literature (2008-2013) describing the applications of thiazole and its derivatives on selected activities. Most of the described compounds are shown to have potential beneficial therapeutic effects, even if all these patents generated few clinical evaluations. However, the thiazole scaffold remains one of great potential for the chemical pharmaceutical research; it can serve for the design of lead compounds especially in cases where the target is known and the mechanism of action is well defined.

Small-Molecules Targeting Kinases Involved in Pulmonary Hypertension: a Patent Review (2010-2015)

Background: Despite the fact that in recent years, a substantial progress has been made in the treatment of pulmonary hypertension, it is still a severe disease characterized by poor prognosis, and the search for new drugs remains a priority. Current remedies address mainly the vasoconstrictor/vasodilator imbalance in the pulmonary circulation, while the causes of the disease are only moderately affected. Recently, the role of receptor and non receptor kinases in pulmonary hypertension has emerged and these targets were extensively considered for the development of new therapeutic strategies. This review discusses the patents on small-molecules targeting kinases involved in the proliferation/apoptosis imbalance, typically present in pulmonary hypertension. Methods: Bibliographic research for the inventions was carried out using Espacenet and Sci-Finder databases, \u201cpulmonary hypertension and kinases\u201d as research query and the range from 2010 to 2015. Only patents published in English were considered. A qualitative analysis of the contents of each patent was made to examine the reported compounds, the studies performed and the resulting conclusions. Results: The review includes about thirty applications. Moreover, in order to illustrate the pathophisiology of the disease and the mechanisms of the targets, about forty additional papers were reported. Considering that imatinib, a PDGF receptor inhibitor, entered the clinical trials for the treatment of pulmonary hypertension, the first patents were devoted to inhibitors of tyrosine kinase receptors, such as PDGFR and c-Kit. Subsequently, in addition to kinase receptors, the role of other pathways involved in pulmonary hypertension has emerged, and some research groups have focused their attention also on non-receptor kinases. Fifteen patents on this topic reported these new targets and new derivatives. However, in most of the inventions, although the pulmonary hypertension is among the treatable diseases, the compounds were subjected only to antiproliferative assays and not to specific tests on animal models. Conclusion: The studies reported in this review confirm the continuous research efforts aimed to identify new targets and new drugs for the treatment of pulmonary hypertension. Several inhibitors of kinase were described. These compounds could inhibit mainly important branching processes and pathological growth of blood vessels, thereby might increase the lifespan of patients

Imidazo[2,1b ] Thiazole: Introduction, Current and Perspective

Imidazo[2,1-b]thiazole is a fused heterobicyclic system containing bridgehead nitrogen atom. Derivatives of this scaffold are especially attractive in the field of medicinal chemistry because of their broad spectrum of biological activities. The imidazo[2,1-b]thiazole system constitutes the core unit of the well-known anthelminthic and immunomodulatory agent Levamisole, marketed under the trade name Ergamisol© and discovered at Janssen Pharmaceutica in 1966

Small-Molecules Targeting Sirtuin 1: A Patent Review (2012-2015)

Sirtuins are a family of enzymes, which govern genome regulation, stress response, metabolic homeostasis and lifespan. Among all the discovered human isoforms (SIRT1-7), SIRT1 emerged as a promising molecular target for the treatment of several diseases. The SIRT1 activators have shown beneficial effects in diabetes, obesity, disorders related to aging, cardiovascular and neurodegenerative diseases. On the other hand, SIRT1 inhibition could be applied in anticancer therapy. This review is focused on patents regarding small molecules targeting SIRT1 registered from 2012 to 2015. The chemical formula, the activation and/or inhibition activity and the application of the most active compounds are considered

On the reactivity of nitrosoimidazoles with acids (the Cusmano–Ruccia reaction): a continuous source of new ring-into-ring interconversion

An extension of the ‘Cusmano–Ruccia’ reaction is reported. 6-(4-chlorophenyl)-3-methyl-5-nitrosoimidazo[ 2,1-b]oxazole by the action of hydrochloric acid gives 3-(4-chlorobenzoyl)-5-methyl-1,2,4-oxadiazole (13); presumably via ammonium ion, CO2 and methanol elimination. The relevance of the nature of the atom of the B-ring linked to C-2 of the imidazole for the occurrence of the ring-into-ring interconversion has been once more confirmed