Studies On The Design,Synthesis Of 2-Aminothiazole Derivatives And Their Pharmacological Activities

Thiazoles as well as imidazoles and oxazoles are members of the azole heterocycles.The thiazole ring is planar and aromatic which have five members containing one sulfur and one nitrogen atoms at position-1 and-3,respectively.A thiazole ring is naturally found in vitamin B1 and penicillin,simultaneously,thiazole skeletons are widely used as parent rings in various chemical materials such as drugs,biocides,fungicides,dyes and chemical reaction catalysts.2-aminothiazole(2-AT)as bioisosteres of phenol or catechol is very stable and lipophilic heterocyclics in the field of pharmaceutical chemistry.Because it posses S-C=N toxophoric unit,thiazole and its derivatives exhibiting boundaryless biological activities,like anticancer,antibacterial,anti-inflammation,anti-HIV,antiprotozoal,antimalarial.They were also being used in the treatments of allergies,schizophrenia,and hypertension antihypertension.Therefore,six series of 79 compounds containing the 2-amino thiazole ring with variable substituents were synthesized as target structures.All the newly synthesized compounds were unreported,the structures were determined on the basis of spectroscopic data such as 1H NMR,13C NMR and HRMS.Some target compounds were evaluated for their in vitro antibacterial activities against four bacterial strains,including Staphylococcus aureus,Bacillus subtilis,Escherichia coli,Pseudomonas aeruginosa by the broth microdilution assay method in 96-well microtest plates.While the anticancer activities against human lung adenocarcinoma cells A549 and human colon cancer cell line HT29 were evaluated by the MTT-based assay.Fristly,[4-(2-aminothiazol-4-yl)phenoxy]acetonitrile compounds(series Ⅰ and Ⅱ)were designed on the basis of the structure of antibacterial agent oxazolidinone.Conformational analysis shows a favorable overlap between Z1 or Z17 and linezolid.The required 4-(2-aminothiazol-4-yl)phenol was easily synthesized by reacting α-bromo-p-hydroxyacetop-henone with thiourea according to the modified Hantzch reaction.Without further purification,4-(2-aminothiazol-4-yl)phenol and excess bromoacetonitrile led to 87%yield of the[4-(2-aminothiazol-4-yl)phenoxy]acetonitrile derivatives.Subsequently,a series of phenyl thiazolyl amide derivatives were obtained by the acylation of acetonitrile derivatives with substituted acid chloride/anhydride.While,acetonitrile derivatives reacted with various aromatic isocyanate compounds afford the phenyl thiazolyl urea derivatives.The results of antimicrobial activity show that the thiazolyl-N-substituted amide derivatives showed better antibacterial activity compared with those corresponding substituted phenyl thiazolyl urea analogs.The compounds were particularly active against gram-positive bacteria Compounds Z6,Z7 and Z16 displayed the potent antibacterial activity.The presence of halogen groups such as chloro or fluoro enhanced the antibacterial activity of newly synthesized compounds.Secondly,the amide and urea derivatives of 4-substituted phenylthiazol-2-amine(seriesⅢ and Ⅳ)were designed according to the pharmacophore characteristics of the protein tyrosine kinase Type Ⅱ inhibitor.The condensation-cyclization of the starting appropriate nitro substituted 2-bromo-1-phenylethanone with thiourea afforded a good yield of 4(3-nitrophenyl)thiazol-2-amine.4-(3-aminophenyl)thiazol-2-amine was generated by treatment of nitro compounds with reducing reagent Fe/NH4Cl in refluxing aqueous ethanol.Under different conditions,the amine derivatives reacted with a different substituted acid chloride/anhydride or a different substituted phenyl isocyanate to give the target compounds.Except for Z31,the series of compounds show better inhibition to the HT29 cell line than A549.The activity difference between the amide derivatives and the ureido derivatives is not conspicuous,introducing a larger aryl group or an amide chain containing oxygen atom to 2amino group of the thiazole ring is not favorable.Finally,based on the combination principles,the structures of GRP78 inhibitor HA15 and sorafenib were fused,some novel N-(4-substituted phenylthiazol-2-y)acetamide derivatives(Series Ⅴ and Ⅵ)were prepared.Synthetic procedures were similar to series Ⅲand Ⅳ,but after the cyclization reaction,the amino group on the thiazole ring was acylated with acetic anhydride firstly.Then the nitro compounds were reduced,the resulting aniline derivatives reacted with the acid chloride/anhydride or isocyanate/isothiocyanate to give final products.Most of the compounds showed potent activities,especially compounds Z53 and Z68 exhibit remarkable antitumor effect against HT29 and A549 cells.Western blot study revealed that the compound Z53 can inhibit the expression of phosphorylated BRAF,CRAF and ERK,which was similar to the mechanism of sorafenib.The results of molecular docking show that BRAF kinase may be the target of the series.