Synthesis of novel 2, 3, 5-tri-substituted thiazoles with anti-inflammatory and antibacterial effect causing clinical pathogens.

BACKGROUND: The present work is an extension of ongoing efforts toward the development and identification of new molecules as monotherapy displaying anti-inflammatory and anti-infective activities and a wide-range of gastrointestinal selectivity. A series of novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and evaluated for their in-vitro and in-vivo anti-inflammatory activities. Synthesized trisubstituted thiazole compounds were also evaluated for their potential antibacterial activity against clinical pathogens causing infectious disease. MATERIAL AND METHOD: The structures of synthesized compounds were characterized by FTIR, 1H NMR, Mass spectroscopic techniques and evaluated for their in-vitro and in-vivo anti-inflammatory effects using the human red blood cell (HRBC) membrane stabilization method and a carrageenan-induced rat paw oedema model, respectively, Diclofenac sodium and Ibuprofen were used as standard drugs. The synthesized compounds AR-17atoAR-27a screened for their in-vitro antibacterial activity against the gram-positive bacteria Staphylococcus aureus (ATCC25923) and Enterococcus faecalis (ATCC29212) and the gram-negative bacteria Escherichia coli (ATCC8739) and Pseudomonas aeruginosa (ATCC9027) using ciprofloxacin and cefdinir as standard drugs. RESULT: Compounds AR-17a and AR-27a elicited maximum anti-inflammatory activity, providing 59% and 61% protection at 20mg/kg, respectively, in the inflamed paw model. Among the tested compounds, AR-17a (6.25), (54) and AR-27a (1.56), (52) had the least minimum inhibitory concentration values and the highest zone of inhibition, indicating their marked antibacterial activities. The lowest conc. were observed at 1.56, 6.25µg/mL for inhibition of bacteria by most of the compounds. CONCLUSION: Novel set of trisubstituted thiazole compounds (AR-17a to AR-27a) have synthesized and characterized successfully. The preliminary screening revealed that these compounds possess promising anti-inflammatory and antibacterial activities. In addition, the objective of the study was achieved with few of the promising structures like AR-17a to AR-27a, which are prove to be potential monotherapy candidates for the treatment of chronic inflammatory diseases and bacterial infections.

Design, synthesis and pharmacological evaluation of novel tetrasubstituted thiophene analogues as anti-inflammatory agents.

A new series of tetrasubstituted thiophene analogues (4a-4f, 5a-5f and 8a-8i) were designed incorporating the pharmacophoric features of COX-1 (as in fenamates), 5-LOX and the p38 MAP kinase inhibitors. The designed series was synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2) yielding the addition product l-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3/7); which on reaction with substituted phenacyl bromides gave the targeted tetrasubstituted thiophene esters (4a-4f / 8a-8i). The tetrasubstituted thiophenes esters (4a-4f ) on hydrolysis with one equivalent of potassium hydroxide solution in methanol at room temperature gave corresponding acids (5a-5f ). All the targeted compounds were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40 mg/kg body weight using standard drugs mefanamic acid and ibuprofen. The compounds (4c, 4e, 4f, 5f, 8a- 8i) which gave reasonable protection to the inflamed paw, eliciting good or moderate comparable anti-inflammatory activity were selected for investigating their analgesic activity using acetic acid induced writhing response test in albino mice at 10 mg/kg dose using standard drug ibuprofen and in order to arrive at possible mechanism of their anti-inflammatory activity, in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL were performed using standard drug ascorbic acid.

Synthesis, anti-inflammatory, analgesic and antioxidant activities of some tetrasubstituted thiophenes.

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC(50) value 31.59 microg/mL.

Syntheses of new tetrasubstituted thiophenes as novel anti-inflammatory agents.

A series of new tetrasubstituted thiophenes (4a-4i, 5a-5i and 6a-6f) have been synthesized as novel anti-inflammatory agents and were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40mg/kg body weight. Among ester series, the best compound 4c showed 71% protection at 10mg/kg, 72% at 20mg/kg, and 76% at 40mg/kg to inflamed paw; while in acid series 5a showed 79% protection at 10mg/kg, 80% at 20mg/kg, and 70% at 40mg/kg, and 5c showed 72% protection at 10mg/kg, 75% at 20mg/kg, and 69% at 40mg/kg, to inflamed paw. In case of oxime series 6a-6f, the anti-inflammatory activities of the candidates were found to be poor as compared to acid and ester series. It was found on the basis of SAR studies of target compounds, that the presence of OCH(3) at R(2) position and H, OCH(3) at R(1) are one of the requirements for eliciting comparable anti-inflammatory activity in both tetrasubstituted thiophenes' ester and acid series. Compounds 4a-4i, 5a-5i were investigated for their analgesic activity in acetic acid induced writhing response model at 10mg/kg dose. Among the ester series compound 4e showed maximum protection of 60%, while 4a, 4b, and 4i exhibited 55%, 45%, and 43% protection, respectively. The result showed that presence of H, Cl at R(1) and OCH(3), CH(3) at R(2) in tetrasubstituted thiophene ester series enhances their analgesic activity. The candidates of acid series 5a-5i showed poor analgesic activity as compared to the standard drug ibuprofen. Compounds 4a-4i, 5a-5i were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay. Among the ester series 4a showed maximum in vitro nitric oxide radical scavenging activity having IC(50) value 30.08microg/ml while in acid series 5a has IC(50) value 25.20microg/ml. The results showed that the presence of R(1)=H, R(2)=OCH(3) and R(1)=R(2)=OCH(3) enhances nitric oxide radical scavenging property in tetrasubstituted thiophenes' acid series.