The Synthesis, Crystal Structure And Biological Activity Of Aryl Thiazole/Thiazine Derivatives

Influenza caused by virus H1N1, H5N1 of type A is a kind of disease with highly contagious acute viral infection of the respiratory. And it’s a big threaten to the health of person. Influenza virus neuraminidases (NA) inhibitors can inhibit influenza virus A and B selectively. And NA inhibitors are the most effective drugs to treat influenza H1N1, H1N5 virus. NA has a relatively conservative in influenza virus mutation process which makes it a good target. However, influenza viruses can develop resistance to the’Tamiflu’via point mutations in NA. The recent emergence of Tamiflu-resistant strains has raised serious concerns about a global flu pandemic because of their potential lethality to humans. So it’s very necessary to research new NA inhibitor. The mapping analyses revealed the presence of novel druggable hot spots in the 150-and 430-loop regions, providing further support for the feasibility of developing high-affinity inhibitors capable of binding these areas. Such inhibitors may be applicable to the group-1 NA’s including N1, N4, N5, and N8, which have nearly identical active site regions, but not necessarily group-2 enzymes (N2, N3, N6, N7, and N9), which appear to lack such well defined cavities. The paper designed and synthesized a series of 3-thiazole-ethyl benzoate,1,3-thiazine NA inhibitors against the double-binding-site of SA/150-Cavity,150-Cavity/430-Cavity and SA/430-Cavity of the open conformation of N1 from influenza virus H1N1. All compounds were evaluated against the inhibitory activity of NA in vitro.1) NA inhibitor against SA/150-Cavity double-binding-site.The first chapter designed and synthesized a series of ethyl benzoate NA inhibitors against SA and 150-Cavity double-binding-site. Though the compound ethyl 4-(N-acetyl-amino)-3-aminobenzoate 1 as intermediate, using the thiazole, urea, amide connect the ethyl 4-(N-acetylamino)-benzoate against SA binding sites and substituted aryl against 150-Cavity binding sites, in order to give more effective NA of H1N1 inhibitor.The intermediate ethyl 4-(N-acetyl-amino)-3-aminobenzoate 1 was synthesized by esterification, acylation, nitration, reduction from the compound 4-amino benzoic acid, and the every step has been optimized. Using microwave heating instead of traditional electric heating in the esterification reaction and using Pd-C as the catalyst in the reduction, give the compound 1 in high yield.Using the 3-aminothiazole connect the ethyl 4-(N-acetylamino)-benzoate against SA binding sites and substituted aryl against 150-Cavity binding sites. A series of ethyl 4-(N-acetylamino)-3-aryl-thiazol-yl-benzoate derivatives had been synthesized though the compoundα-bromo-1-arylketones reacted with compound 6. Discussing the influence of different pH values to the reaction, and get the target product at pH=5-9, and benzimidazoles is hard to prepared at this pH.Using the urea connect the ethyl 4-(N-acetylamino)-benzoate against SA binding sites and substituted aryl (or alkyl) against 150-Cavity binding sites. A series of ethyl 4-(N-acetyl amino)-3-(aryl or alkyl-urea)-yl-benzoate and 4-(N-acetylamino)-3-(aryl or alkyl-urea)-yl-benzoic derivatives had been synthesized though the compound a-bromo-1-arylketones reacted with compound 1 in the yield 69.0%-86.4%.Using the acetylamino connect the ethyl 4-(N-acetylamino)-benzoate against SA binding sites and substituted aryl(or alkyl) against 150-Cavity binding sites. A series of ethyl 4-(N-acetylamino)-3-(aryl or alkyl-acetylamino)-yl-benzoate and 4-(N-acetylamino)-3-(aryl or alkyl-acetylamino)-yl-benzoic derivatives had been synthesized though the compoundα-bromo-1-arylketones reacted with compound 1 in the yields 22.8%-87.4%.2) NA inhibitor against 150-Cavity/430-Cavity double-binding-site.The second chapter designed and synthesized a series of 1,3-thiazine derivatives as NA inhibitors against 150-Cavity/430-Cavity double-binding-site. Using 1,3-thiazine rings connected two big hydrophobic groups alkyl and aryl. The compounds were evaluated the inhibitory activity against NA of H1N1 in vitro, and found 1,3-thiazine derivatives having good activity.A series of 2-Amino-6-aryl-4-teriarybutyl-1,3-thiazine-hydrochlorid have been synthesized though the 4,4-dimethyl-l-aryl-l-en-3-one reacting with thiourea in the yield of 28.2%-92.8%. Compared the five different acid such as BF3·Et2O, AlCl3, conc. HCl, H2SO4, HNO3, CH3COOH catalyzing Biginelli reaction, we chose conc. HCl as the finally catalyst. The structures of compound 44 and 77 were been confirmed by X-ray, The molecules of compound 44 are packed in an offset face-to-face arrangement showingπ-πstacking interaction involving the benzene rings. The molecules of compound 77 are stabilized by N-H…Cl hydrogen bond.3) NA inhibitor against SA/430-Cavity double-binding-siteThe third chapter chose 1,3-thiazine ring as the core ring against SA, designed and synthesized a series of 1,3-thiazine inhibitors against SA and 430-Cavity double-binding-site. Piperidine was selected as the catalyst in the Knoevenagel reaction. A series of 2-arylenzilidene ethyl acetoacetate have been synthesized in the yields of 42.1%-75.8%. Most of the compounds were given by chromatography. In the process of synthesizing compounds of ethyl 2-acetylamido(or amino-4-methyl-6-aryl-1,3-thiazine-5-carboxylate, water segregator was been used, ethanol was selected as the solvent. Water and some ethanol azeotropic reaction can remove the by-product water from the system. Thus enhancing the reaction yield of compound and shortening the reaction time to 7 hours.The structures of Ethyl 2-acetamido-6-(3-methoxyphenyl)-4-methyl-6H-1,3-thiazine-5-carboxylate (98) was been confirmed by X-ray. The molecules of compound 98 are stabilized by N—H…O hydrogen bond.4) Biological ActivityThe NA inhibitory activity in vitro of all the synthesized compound were tested at 40μg/mL, Most of the synthesized compounds have good activity against NA of H1N1. Several compounds against double-binding-site are more effective than the compounds against SA binding site reported. The potential compounds 71 and 98 had the IC50 0.07μmol/mL and 0.07μmol/mL respectively, which could be used as lead compounds in future.The bactericidal, insecticidal, herbicidal activity of thiazole compounds 8-25 and thiazine derivatives 67-76 were been tested by Bayer company. All the selected compounds have no insecticidal activity. The Compound D from thiazole compounds 8-25 had good herbicidal activity against MATCH, can be a wonderful herbicidal chemical. The compound A from thiazole compounds 8-25 had ED50=46μg/mL against LEPTNO. The Compound H from thiazole compounds 8-25 had ED50=28.2μg/mL against LEPTNO. The two compounds could be good bactericidal chemicals.