Synthesis And In Vitro Antibacterial Evaluation Of New Thiazole Amide Compounds

As a kind of invasive pathogen, various parasites cause serious economic loss and impose serious threat to the health of human beings and livestock. However, antiparasitic drugs available in the market are less species, with serious side effects and drug resistance. Effective antiparasitic drugs with fewer side effects, low residual properties are now becoming the interesting research spots.Nitazoxanide, a new broad-spectrum antiparasitic drug, have shown significant activities against parasites, bacteria and viruses. Studies have shown that the nitro thiazole ring is necessary for nitazoxanide’s remarkable biological activities. Chalcones, widely existed in natural products, were found to be possessed various biological activities especially antiparasitic effects.According to the principle of combination of pharmacophores, we designed and synthesized two series of thiazolide compounds, bisamides and chalcone thiazole amides. Anaerobic bacteria and anaerobic parasites both have the key enzyme-pyruvate:ferredoxin oxidoreductase(PFOR) in the process of energy metabolism.The mechanism of action for NTZ is associated with inhibition of PFOR. Therefore in vitro antibacterial activities of designed compounds were investigated including anaerobic bacteria Clostridium Difficile. Meanwhile, compounds with high activities can serve as promising lead compounds for new drug development against parasites.Synthesis of novel bisamides compounds. Compound 2a, 2b and 2c were prepared from amino diol and corresponding arylmethyl halides through a nucleophilic substitution reaction with excess K2CO3 as a base in proper amount acetone. Chloroacetic acid aromatic amides(3, 4 and 5) were prepared in good yields from chloroacetic chloride and aromatic amines according to routine process. The final designed bisamides(6a-c、7a-c、8a-c) were prepared through a nucleophilic substitution reaction with NaH as base. Structures of the intermediates and target compounds were confirmed by 1H-NMR, 13C-NMR and HR-MS.Synthesis of novel chalcone thiazolyl amide compounds. Corresponding substituted phenyl acryloyl benzoic acid A1-A12 were prepared through a classical Claisen-Schmidt reaction with substituted benzaldehyde and 4-acetyl benzoic acid as starting materials. Without further purification, A1-A12 coupled with 2-amino-5-nitrothiazole in the presence of HOBt, EDCI and DIPEA in anhydrous THF, which finally giving moderate yield of designed B1-B12. Structures of the intermediates and target compounds were confirmed by 1H-NMR and HR-MS.In vitro antibacterial evaluation of target compounds. MIC values of compounds 6a-c、7a-c、8a-c、A1-A12、 B1-B12 against Clostridium Difficile, Clostridium Perfringens was measured by the means of agar dilution method. For Escherichia Coli and Staphylococcus Aureus, broth dilution method was applied. The results showed that most of the bisamides have poor activity against all the bacterias with MIC values high than 32 μg/mL. However, for intermediates A1-A12 and Chalcone thiazole amides B1-B12, several compounds shown significant antibacterial activity against Clostridium difficile and Clostridium perfringens. B10 and B11 exhibited considerable activities against with Clostridium difficile compared to nitazoxanide and metronidazole, with MIC values of 2 μg/mL and 1 μg/mL respectively. All the compounds showed little inhibition effect on Escherichia Coli and Staphylococcus Aureus except A9 and A12.