Substituted 4-phenylthiazoles: Development of potent and selective A1, A3 and dual A1/A3 adenosine receptor antagonists.

Adenosine acts as a powerful signaling molecule via four distinct G protein-coupled receptors, designated A1, A2A, A2B and A3 adenosine receptors (ARs). A2A and A2B ARs are Gs-coupled, while A1 and A3 ARs inhibit cAMP production via Gi proteins. Antagonists for A1 and A3 ARs may be useful for the treatment of (neuro)inflammatory diseases including acute kidney injury and kidney failure, pulmonary diseases, and Alzheimer's disease. In the present study, we optimized the versatile 2-amino-4-phenylthiazole scaffold by introducing substituents at N2 and C5 to obtain A1 and A3 AR antagonists including dual-target compounds. Selective A1 antagonists with (sub)nanomolar potency were produced, e.g. 11 and 13. These compounds showed species differences being significantly more potent at the rat as compared to the human A1 AR, and were characterized as inverse agonists. Several potent and selective A3 AR antagonists, e.g. 7, 8, 17 and 22 (Ki values of 5-9 nM at the human A3 AR) were prepared, which were much less potent at the rat orthologue. Moreover, dual A1/A3 antagonists (10, 18) were developed showing Ki values between 8 and 42 nM. Docking and molecule dynamic simulation studies using the crystal structure of the A1 AR and a homology model of the A3 AR were performed to rationalize the observed structure-activity relationships.

An asymmetric alkynylation/hydrothiolation cascade: an enantioselective synthesis of thiazolidine-2-imines from imines, acetylenes and isothiocyanates.

A multicomponent reaction between imines, terminal alkynes, and isothiocyanates in the presence of a catalytic chiral copper-pybox complex proceeds enantioselectively to give enantiopure thiazolidine-2-imines (60-99% ee) via a highly regioselective intramolecular 5-exo-dig hydrothiolation reaction.

Base-mediated hydroamination of propargylamine: a regioselective intramolecular 5-exo-dig cycloisomerization en route to imidazole-2-thione.

An intramolecular transition-metal-free base-mediated hydroamination of propargylamine with isothiocyanates has been achieved. This atom-economical, regioselective intramolecular 5-exo-dig cycloisomerization was utilized for the one-pot synthesis of diversely substituted imidazole-2-thione and spiro-cyclic imidazolidine-2-thione. The reaction goes to completion at room temperature via propargylthiourea and 65-97% isolated yields were obtained.

2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists.

A series of 2-amino-5-benzoyl-4-phenylthiazole derivatives was investigated in radioligand binding studies at adenosine receptor (AdoR) subtypes with the goal to obtain potent and A(1)-selective antagonists. Acylation of the 2-amino group was found to be crucial for high A(1) affinity. The best compound of the present series was 2-benzoylamino-5-p-methylbenzoyl-4-phenylthiazole (16 m) showing a K(i) value of 4.83 nM at rat and 57.4 nM at human A(1) receptors combined with high selectivity versus the other AdoR subtypes. The compound behaved as an antagonist in GTP shift assays at A(1) receptors. Compound 16 m may serve as a new lead structure for the development of second-generation non-xanthine-derived A(1) antagonists which have potential as novel drugs.

2-Amino-5-thiazolyl motif: a novel scaffold for designing anti-inflammatory agents of diverse structures.

Substituted thiazoles with different structural features were synthesized and screened for their anti-inflammatory activity in acute carrageenin induced rat paw edema model and chronic formalin induced rat paw edema model. The compounds 1-5 showed 83, 30, 63, 69 and 73% protection, respectively, in acute carrageenin induced rat paw edema model. In 5-day chronic formalin induced rat paw edema model on the fifth day 1 and 5 gave 66 and 41% protection. Both studies were carried out at a dose of 100mg/kg body weight. The activity was compared with that of Ibuprofen, Rofecoxib, and Dexamethasone both in acute and chronic anti-inflammatory models. Compound 1 without COX-1 and COX-2 inhibitory activity showed good activity profile almost mimicking the gold standard Dexamethasone in terms of efficacy. A 7-day study in rats at dose of 100mg/kg showed that this compound does not have any ulcerogenic activity and toxicity. The activity of 5 shows that incorporating two pharmacophoric features in one molecule can be a good drug designing strategy. 2,4-Diaminothiazoles with an aliphatic oxime esters attached via a ketone bridge to the 5th position of thiazole was identified as a novel scaffold for designing anti-inflammatory agents.

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.