Anti-inflammatory action of new hybrid N-acyl-[1,2]dithiolo-[3,4-c]quinoline-1-thione.

Most of pharmaceutical agents display a number of biological activities. It is obvious that testing even one compound for thousands of biological activities is not practically possible. A computer-aided prediction is therefore the method of choice in this case to select the most promising bioassays for particular compounds. Using the PASS Online software, we determined the probable anti-inflammatory action of the 12 new hybrid dithioloquinolinethiones derivatives. Chemical similarity search in the World-Wide Approved Drugs (WWAD) and DrugBank databases did not reveal close structural analogues with the anti-inflammatory action. Experimental testing of anti-inflammatory activity of the synthesized compounds in the carrageenan-induced inflammation mouse model confirmed the computational predictions. The anti-inflammatory activity of the studied compounds (2a, 3a-3k except for 3j) varied between 52.97% and 68.74%, being higher than the reference drug indomethacin (47%). The most active compounds appeared to be 3h (68.74%), 3k (66.91%) and 3b (63.74%) followed by 3e (61.50%). Thus, based on the in silico predictions a novel class of anti-inflammatory agents was discovered.

Computer-aided discovery of pleiotropic effects: Anti-inflammatory action of dithioloquinolinethiones as a case study.

Most of pharmaceutical agents exhibit several or even many biological activities. It is clear that testing even one compound for thousands of biological activities is a practically not feasible task. Therefore, computer-aided prediction is the method-of-the-choice to select the most promising bioassays for particular compounds. Using PASS Online software, we determined the likely anti-inflammatory action of the 13 dithioloquinolinethione derivatives with antimicrobial activities. Chemical similarity search in the Cortellis Drug Discovery Intelligence database did not reveal close structural analogues with anti-inflammatory action. Experimental testing of anti-inflammatory activity of the synthesized compounds in carrageenan-induced inflammation mouse model confirmed the computational predictions. The anti-inflammatory activity of the studied compounds was comparable with or higher than the reference drug Indomethacin. Thus, based on the in silico predictions, novel class of the anti-inflammatory agents was discovered.

Docking analysis targeted to the whole enzyme: an application to the prediction of inhibition of PTP1B by thiomorpholine and thiazolyl derivatives.

PTP1b is a protein tyrosine phosphatase involved in the inactivation of insulin receptor. Since inhibition of PTP1b may prolong the action of the receptor, PTP1b has become a drug target for the treatment of type II diabetes. In the present study, prediction of inhibition using docking analysis targeted specifically to the active or allosteric site was performed on 87 compounds structurally belonging to 10 different groups. Two groups, consisting of 15 thiomorpholine and 10 thiazolyl derivatives exhibiting the best prediction results, were selected for in vitro evaluation. All thiomorpholines showed inhibitory action (with IC50 = 4-45 µΜ, Ki = 2-23 µM), while only three thiazolyl derivatives showed low inhibition (best IC50 = 18 µΜ, Ki = 9 µΜ). However, free binding energy (E) was in accordance with the IC50 values only for some compounds. Docking analysis targeted to the whole enzyme revealed that the compounds exhibiting IC50 values higher than expected could bind to other peripheral sites with lower free energy, Eo, than when bound to the active/allosteric site. A prediction factor, E- (ΣEo × 0.16), which takes into account lower energy binding to peripheral sites, was proposed and was found to correlate well with the IC50 values following an asymmetrical sigmoidal equation with r2 = 0.9692.

Thiazoles and thiazolidinones as antioxidants.

Antioxidants are of great interest because of their involvement in important biological and industrial processes. According to Halliwell antioxidants are substances that at low concentration significantly delay or prevent oxidation. Chemically, oxidation is a process in which a loss of electrons occurs. Oxidants play a significant role in the pathogenesis of a number of disorders leading to oxidative stress. Oxidative stress may be defined as an imbalance between cellular production of reactive oxygen species and antioxidant defense mechanisms. ROS (e.g., superoxide radical, peroxynitryl, hydroxyl radical and hydrogen peroxide) are constantly produced as a result of metabolic reactions in living systems. Oxidative damage caused by ROS is responsible for many degenerative diseases such as cancer, atherosclerosis, diabetes, cirrhosis, Alzheimer's and inflammatory diseases. The aim of this review is to describe recent developments in the study of the antioxidant activity of thiazole and thiazolidinone derivatives, which are the core structure in a variety of pharmaceuticals with a broad spectrum of biological activity and their role in preventing the formation of ROS.

Synthesis of some new thienyl and 1,3-thiazolyl-aminoketones with anti-inflammatory activity.

Eight thienyl and 1,3-thiazolyl-aminoketones were synthesised and tested as anti-inflammatory agents. pKa and log P were theoretically calculated. The compounds were tested for antioxidant activity, as hydroxyl radical scavengers, as superoxide anion scavengers and for their ability to interact with 1,1-diphenyl-2-picryl hydrazyl stable free radical (DPPH). The effects of the synthesised compounds on inflammation were studied using the carrageenan induced mice paw oedema model. Both anti-inflammatory and antioxidant activities depended on some structural characteristics of the synthesised compounds.

Synthesis of some new aroyl/aryloxy-2-amino-1,3-thiazole derivatives with anti-inflammatory activity.

The synthesis of some novel aroyl/aryloxy aminothiazoles from the appropriate gamma-chloro-butyrophenones, gamma-chloro-butyrothienones, gamma-chloro-aryloxypropanes with the corresponding substituted 2-amino-1,3-thiazoles is described. The spectroscopical data (UV, IR, 1H-NMR and MS) of the derivatives are presented.

Thiazolyl and benzothiazolyl Schiff bases as novel possible lipoxygenase inhibitors and anti inflammatory agents. Synthesis and biological evaluation.

Several thiazolyl derivatives are reported to act as lipoxygenase inhibitors affecting inflammation and/or psoriasis. Two series of new thiazolyl and benzothiazolyl Schiff bases have been designed, synthesized and identified. RM values were determined as an expression of lipophilicity. The compounds were screened for their reducing activity (with the stable free radical 1,1-diphenyl-2-picrylhydrazyl DPPH), for radical scavenging activity (with the xanthine/xanthine oxidase system for O2.-) and for inhibition of soybean lipoxygenase (LO). Anti inflammatory activity was examined in vivo, using the carrageenin induced mice paw edema (24-71.8% inhibition was observed). The results are discussed in terms of structural and physicochemical characteristics of the compounds. Comparing the results among all tests, the benzothiazolyl derivatives seem to be more potent.

Effect of 2,4-disubstituted thiazol-5yl-aminoketones on inflammation. In vitro and in vivo biological studies: a structure-activity approach.

Some modified novel thiazol-5yl-aminoketones were evaluated for their anti-inflammatory, analgesic and antiproteolytic activities. Their inhibitory activity on 12-lipoxygenase (12-LO) and beta-glucuronidase in vitro was estimated. Their interaction with the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) and their RM values were also determined. For two of them, the effect on zoxazolamine-induced paralysis after a prolonged treatment was determined. The duration of paralysis for the same compounds, (only one administration, one before zoxazolamine injection) was recorded too. The 2-amino substituted derivatives seem to be more potent in comparison with the 2-phenyl. The tested compounds were found to influence proteolysis but not the activities at beta-glucuronidase and 12-LO. Their interaction with DPPH was mild. Compound 2 seems to modify the activity of the hepatic drug metabolizing enzymes. In conclusion, their activity is related to certain structural characteristics.

In vitro studies of some 2,4-disubstituted thiazolyl-aminoketones with anti-inflammatory activity. Correlation with lipophilicity and structural characteristics.

A number of ring and chain substituted aminothiazole derivatives with strong anti-inflammatory activity were studied for their antiproteolytic and oxygen radical scavenging properties. Their interactions with the stable free radical 1,1-diphenyl-2-picrylhydrazyl was determined. Their inhibition of the soybean 12-lipoxygenase and beta-glucuronidase enzymes was evaluated. They scavenged superoxide anion and inhibited proteolysis to a non appreciable extent, whereas no activity on beta-glucuronidase and lipoxygenase was found. Their reducing ability was found to be low. Good correlation was obtained between the anti-inflammatory activity and clog P (theoretically calculated lipophilicity) and between anti-inflammatory activity and proteolytic inhibition. RM values were also determined.

Anti-inflammatory activity of some novel 1-[3-(aroylo)] and one 1-[3-(aryloxy)]-propyl aminothiazole in correlation with structure and lipophilicity.

The effect of some new 1-[3-(aroylo)] and one 1-[3-[aryloxy)]-propyl aminothiazole on inflammation was investigated in the carrageenin-induced mouse paw edema (36-58% edema inhibition). In addition they exhibited significant analgesic activity (55-80.6%) in the writhing test. Their antioxidant activity in vitro using the stable free radical 1.1-diphenyl-2-picrylhydrazyl (DPPH), was determined. Antiproteolytic ability and beta-glucuronidase inhibition have been studied. The tested compounds did not inhibit soybean 12-lipoxygenase. RM values, as an expression of lipophilicity, were determined.