The first Q-Tube based high-pressure synthesis of anti-cancer active thiazolo[4,5-c]pyridazines via the [4 + 2] cyclocondensation of 3-oxo-2-arylhydrazonopropanals with 4-thiazolidinones

Abstract

A novel and efficient protocol for the synthesis of thiazolo[4,5-c]pyridazine derivatives was developed. The approach utilizes a high pressure Q-Tube reactor to promote cyclocondensation reactions between 3-oxo-2-arylhydrazonopropanals and 4-thiazolidinones. The process has a significantly high atom economy and a broad substrate scope, as well as being applicable to gram scale syntheses. The in vitro cytotoxic activities of the synthesized thiazolo[4,5-c]pyridazine derivatives were examined utilizing a MTT colorimetric assay with doxorubicin as a reference anti-cancer drug and three human cancer cell lines including HCT-116 (colon), MCF-7 (breast) and A549 (lung). The results show that thiazolopyridazines 7c, h, k and p have high cytotoxic activity against the MCF-7 cell line with respective ic 50 values of 14.34, 10.39, 15.43 and 13.60 μM. Moreover, the thiazolopyridazine derivative 7s also show promising cytotoxic activity against the HCT-116 cell line with IC 50 = 6.90 μM . Observations made in this effort serve as a basis for further investigations into the design and preparation of new anti-cancer drugs.Thiazolopyridazine derivatives comprise a broad range of structurally interesting substances that display a variety of medicinally interesting properties including activities against cancers 1,2 , microbes 3,4 , viruses 5 and bacteria 6 , as well as antioxidant 7 , analgesic and pesticidal activities 8,9 . As a result of these important properties, thiazolopyridazines remain the focus of our continuing investigations aimed at developing new and green routes for the synthesis of novel fused nitrogen containing heterocycles [10][11][12][13][14][15][16][17][18] . Until now, several methods have been developed for the synthesis of fused thiazolopyridazines, most of which are targeted at the synthesis of thiazolo[4,5-d] pyridazines 1-3,5 , thiazolo[3,2-b]pyridazine 19 and thiazolo[5,4-c]pyridazine 6 . In contrast, current methods to prepare thiazolo [4,5-c]pyridazines are much less well-developed 20 , and they suffer from some major deficiencies. Specifically, the only method devised for this purpose involves reaction of pyridazine-3-carboxamide derivatives with Lawesson's reagent under reflux for 48 h, which forms mono-substituted thiazolo[4,5-c]pyridazines in only moderate yields (Scheme 1a) 20 .In the current study, we developed a novel and efficient green method for the synthesis members of a series o thiazolo[4,5-c]pyridazine derivatives. The new protocol, which involves cyclocondensation reactions between 4-thiazolidinones and 3-oxo-2-arylhydrazonopropanals utilizing a high pressure Q-Tube reactor, is simple and environmentally benign (Scheme 1b). In contrast to those utilizing microwave irradiation and conventional heating, processes carried out using the Q-Tube reactor employ a high pressures to promote organic reactions. Use of the Q-tube technique has many advantageous features 21-28 including higher yields, clean products, lower energy costs, lower reaction times and higher reproducibility than those as...

High pressure assisted synthetic approach for novel 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridine and 5,6-dihydrobenzo[h]quinoline derivatives and their assessment as anticancer agents

“…Furthermore, synthetic and drug chemists are attracted by functionalized dihydrobenzo[ h ]quinolines because they are possess some pharmacological activities, including, but not limited to, anti-tumor 28 , anti-cancer 29 , and anti-bacterial activity 30 . As a result of these elegant applications and features and in the continuation of our efforts to develop novel protocols for synthesizing N -containing heterocycles 31 – 42 , 6,7-dihydro-5 H -benzo[6,7]cyclohepta[1,2- b ]pyridine and 5,6-dihydrobenzo[ h ]quinoline have attracted our attention. After careful literature survey, several methods have been developed to synthesize these two classes of compounds 16 – 18 , 43 , 44 , but to the best of our knowledge, this is the first route that includes the 3-oxo-2-arylhydrazonopropanals as starting material and the Q-tube reactor.…”

Green Protocol for the Novel Synthesis of Thiochromeno[4,3-b]pyridine and Chromeno[4,3-b]pyridine Derivatives Utilizing a High-Pressure System

“…A little attention has been paid toward the biologically active thiochromeno­[2,3- b ]­pyridine derivatives , where few synthetic routes for some examples of thiochromeno­[2,3- b ]­pyridines were published. − Apart from this, only one publication for the synthesis of the thiochromeno­[4,3- b ]­pyridine skeleton was reported via a multicomponent reaction of thiochromanone with dimethylformamide-dimethylacetal and ethyl acetoacetate in the presence of ammonium acetate . In continuation to our work which aimed at developing new synthetic routes for new heterocyclic compounds, − herein the Q-tube reactor was used in this study. In comparison with conventional heating, the Q-tube reactor has several characteristics and features − including (1) better yield and performance, (2) a cleaner product profile that means light color and less impurities and byproducts, (3) energy savings, lower reaction time, and higher reproducibility, and (4) cheaper and safer because the sealing and pressing are easy.…”

High-Pressure Metal-Free Catalyzed One-Pot Two-Component Synthetic Approach for New 5-Arylazopyrazolo[3,4-b]Pyridine Derivatives

“…Due to the diverse applications of the heterocycles that comprise the pyrazolo[3,4- b ]pyridine moiety, developing new protocols for their synthesis is challenging for pharmaceutical and organic chemists. The first Q-tube-mediated, high-pressure strategy for the preparation of an unparalleled series of thiazolo[4,5- c ]pyridazines was recently published by our group [ 19 ]. Consequently, as part of our continued endeavors to develop efficient, environmentally friendly, and expedient protocols, a metal-free catalyst, high-pressure-assisted strategy for synthesizing pyrazolo[3,4- b ]pyridines was explored in the present study.…”