Search

The different reactivity of the chlorine atoms in title dichloronaphthyridine (I) allows the selective synthesis of mono- and diamino-substituted derivatives (III) as well as (V) and (VI), respectively.

9 Title compounds of type (III) are prepared and tested for their anti-inflammatory and psychotropic activities.

Hydrazino derivatives (I) and (VI) undergo ring closure reactions by treatment with triethyl orthoformate (II), formic acid (IV) and nitrous acid to give the title compounds in good yields.

A series of thiazolyl-N-substituted amides were synthesized and tested for anti-inflammatory activity. Their RM values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and log D7.4 was also performed. The effect of the synthesized compounds on inflammation, using the carrageenan-induced mouse paw edema model was studied. In general, the studied compounds were found to be potent anti-inflammatory agents (23.2–72.1%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesized compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure–activity relationship approach (QSAR). A parabolic dependence of activity from clog D7.4 and a linear dependence from surface tension were found. The anti-inflammatory activity of the thiazolyl-amides were found to a great extent to be under pharmacokinetic control. Drug Dev. Res. 48:53–60, 1999. © 1999 Wiley-Liss, Inc.

Computer aided prediction of biological activity spectra has been carried out for 50 new thiazolyl and benzothiazolyl derivatives. Predicted activity spectra for different compounds from the set include 1‐8 activities with estimated probability to be found more than 50%, which cover both possible therapeutic and adverseyside effects. Experimental data coincide with the prediction for 25 of 39 compounds tested as NSAIDs (64.1%); for 4 of 6 compounds tested as local anaesthetics (66.7%); for 1 compound tested as antioxidants (100%). The concordance that describes the overall percentage of correct predictions equals to 65.2% that is sufficient to use this approach for optimization of biological testing. In particular, the compounds from studied data set will be further tested according to the additional predicted activities. Description of the current version of computer system PASS and feasibility for free testing is available via Internet on http://www.ibmh.msk.su/ PASS.

A domino reaction of 1,2-diaza-1,3-dienes with vinyl malonitriles produces unprecedented 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazoles in a chemo- and regioselective fashion.

A series of new N-[(benzo)thiazol-2-yl]-2/3-[3,4-dihydroisoquinolin-2(1H)-yl]ethan/propanamide derivatives was synthesized and characterized by 1H, 13C NMR and IR spectroscopy and mass-spectrometry. A single crystal X-ray study of N-(1,3-benzothiazol-2-yl)-2-[3,4-dihydroisoquinolin-2(1H)-yl]ethanamide is reported to determine its conformational feature. The investigated compounds were found to be active in psychotropic in vivo, anti-inflammatory in vivo and cytotoxicity in vitro screening. They possess marked sedative action, reveal high anti-inflammatory activity, have selective cytotoxic effects and NO-induction ability concerning tumour cell lines. Some of the compounds synthesized demonstrate antimicrobial action. An attempt was made to correlate the biological results with their structural characteristics and physicochemical parameters. Some specific combinations of types of activities for the synthesized compounds have been revealed.

As a part of our ongoing studies in developing new derivatives as dual antimicrobial/anti-inflammatory agents we describe the synthesis of novel 5-arylidene-2-(1,3-thiazol-2-ylimino)-1,3-thiazolidin-4-ones. All newly synthesized compounds were tested for their anti-inflammatory activity using carrageenan mouse paw edema bioassay. Their COX-1/LOX inhibitory activities were also determined. Moreover, all compounds were evaluated for their antimicrobial and antifungal activities against a panel of Gram positive, Gram negative bacteria and moulds. All tested compounds exhibited better antimicrobial activity than commercial drugs, bifonazole, ketoconazole, ampicillin and streptomycin.

The chemistry of the thiobenzothiazine scaffold is utilized, demonstrating a site-selective method for making condensation products of bisphosphonates in satisfactory yields from thiazinethiones (I), (V) and (VII) and tetraethyl methylenebisphosphonate (II).

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.

Reverse transcriptase (RT) inhibitors play a major role in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Although, many compounds are already used as anti-HIV drugs, research on development of novel inhibitors continues, since drug resistant strains appear because of prolonged therapy. In this paper, we present the synthesis and evaluation of HIV-1 RT inhibitory action of eighteen novel (4/6-halogen/MeO/EtO-substituted benzo[d]thiazol-2-yl)thiazolidin-4-ones. The two more active compounds (IC50 : 0.04 µM and 0.25 µM) exhibited better inhibitory action than the reference compound, nevirapine. Docking analysis supports a stable binding of the most active derivative to the allosteric centre of RT. Kinetic analysis of two of the most active compounds indicate an uncompetitive inhibition mode. This is a desired characteristic, since mutations that affect activity of traditional non-competitive NNRTIs may not affect activity of compounds of this series. Interestingly, the less active derivatives (IC5040 µM) exhibit a competitive mode of action.

Methods for the preparation of various aminomethylene bisphosphonates were developed. The required bisphosphonates were obtained by applying tetraethyl methylenebisphosphonate reagent to different types of oxazinones and the relevant Schiff base derivatives. Based on the prediction results (Pass program), we further estimated the sister chromatid exchange frequency and proliferation rate index values of human lymphocyte cultures after the administration of four newly synthesized bisphosphonates in order to evaluate their cytotoxic/cytostatic and possible antineoplastic potency. The results showed that all four bisphosphonates cause a dose-dependent increase in sister chromatid exchange frequency, followed by a decrease in proliferation rate index in both experiments compared to the control.

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.

A series of thirteen new thiadiazole compounds were synthesized and evaluated for in vitro antifungal and antibacterial activity. All compound tested showed significant antifungal activity against all the micromycetes, compared to the commercial fungicide bifonazole. Differences in their activity depend on the substitution of different reactive groups. More specifically, best antifungal activity was shown for the synthetic analogue with methylpiperazine reactive group. Furthermore, it is apparent that different compounds reacted on different ways against bacteria. An effort was made to correlate the above mentioned differences in activity with lipophilicity studies. Furthermore, NMR and molecular modelling were used to obtain the main conformational features of a potent analogue, for future in silico studies.

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

A series of thirteen new thiadiazole compounds were synthesized and evaluated for in vitro antifungal and antibacterial activity. All compound tested showed significant antifungal activity against all the micromycetes, compared to the commercial fungicide bifonazole. Differences in their activity depend on the substitution of different reactive groups. More specifically, best antifungal activity was shown for the synthetic analogue with methylpiperazine reactive group. Furthermore, it is apparent that different compounds reacted on different ways against bacteria. An effort was made to correlate the above mentioned differences in activity with lipophilicity studies. Furthermore, NMR and molecular modelling were used to obtain the main conformational features of a potent analogue, for future in silico studies.

Some numbers of the family of 2-(aminoacetylamino)thiazoles were synthesized. The structure of these compounds was identified both by elemental as well as by spectroscopic analysis (UV, IR, H-NMR, MS). The possible local anaesthetic action of these compounds was also tested using the sciatic nerve of the frog. None of the tested compounds were found to have local anaesthetic action in on in vitro preparations as lidocaine, but one of the compounds showed a similar anaesthetic action to procaine.

Base catalysed condensation of ketone 5 with different aldehydes give chalcones, 2.4-bis-(phenylamino)-6-[4'-{3''-(4'''-substituted phenyl/2'''-furanyl/2'''-thienyl)-2''-propenon-1''-yl}phenylamino]-s-thriazines 6a-e. These chalcones on cyclization with hydrazine hydrate in the presence of glacial acetic acid, guanidine nitrate in the presence of alkali and malononitrile in the presence of ammonium acetate give the corresponding acetylpyrazolines 7a-e, aminopyrimidines 8a-e and cyanopyridines 9a-e respectively. The products 6a-e, 7a-e, 8a-e and 9a-e were fully characterized by spectroscopic and elemental analysis and also tested for antibacterial activity.

A series of adamantane derivatives of thiazolyl-N-substituted amides were synthesized in a three-step reaction and tested for anti-inflammatory activity as well as lipoxygenase and cycloxygenase inhibitory actions. Theoretical calculation of their lipophilicity, as C log P was performed. The effect of the synthesized compounds on inflammation, using the carrageenin-induced mouse paw oedema model was studied and compared to indomethacin. In general, the studied compounds were found to be potent anti-inflammatory agents (29.6–81.5%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesized compounds. The lipoxygenase inhibitory activity was tested by the conversion of sodium linoleate to 13-hydroperoxylinoleic acid. Low inhibitory activity was observed. Evaluation of COX-1 and COX-2 inhibitory activities of the compounds revealed a COX-1 inhibitory potential, comparable to that of naproxen for some of the compounds and a low to moderate COX-2 inhibitory potential. Comparison of the in vivo and in vitro results leads to the conclusion that most compounds of this series may be involved in other mechanisms of inflammation, too.

On the basis of computer prediction of biological activity by PASS and toxicity by DEREK, the most promising 32-alkylaminoacyl derivatives of 3-aminobenzo[d]isothiazole were selected for possible local anaesthetic action. This action was evaluated using an in vitro preparation of the isolated sciatic nerve of the rat and compared with lidocaine which was used as a reference compound. QSAR studies showed that the polarizability, polarity and molecular shape of molecules have a positive influence on their local anaesthetic activity, while contributions of aromatic CH and singly bonded nitrogen are negative. Since the estimated PASS probabilities to find local anaesthetic activity in the most active compounds are less than 50%, these compounds may be considered to be possible NCEs.

A series of 10 new 5-[2-(substituted sulfamoyl)-4,5-dimethoxy-benzyl]-4aryl-s-triazole-3-thiones were synthesized and evaluated for in vitro antifungal and antibacterial activity. All compounds tested showed significant antifungal activity against all the micromycetes, compared to the commercial fungicide bifonazole. Differences in their activity depend on the substitution of different reactive groups. More specifically, best antifungal activity among synthetic analogues was shown with N-dimethylsulfamoyl group. All the compounds tested against bacteria showed the same activity as the commercial agent streptomycin, except for Enterobacter cloacce and Salmonella species. Chloramphenicol showed lower bactericidal effect than the synthetic compounds. Furthermore, it is apparent that different compounds reacted in different ways against bacteria. Gram (-) bacteria seem to be more sensitive to these compounds than Gram (+) species. An effort was made to correlate the above-mentioned differences in activity with lipophilicity studies. Furthermore, molecular modeling was used to obtain the main conformational features of this class of molecules for future structure-activity relationship studies.

Cardiovascular disease remains the leading cause of death worldwide. The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure, through the actions of angiotensin (Ang) II. Excessive RAAS activity may lead to hypertension and associated target organ damage. Indeed, RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT (1) blockers (ARBs) has proved to be successful treatment for arterial hypertension, heart failure and diabetes. Accumulating evidence suggests that arterial stiffness is an important and independent predictor of cardiovascular risk. More recently, a role for advanced glycation end-products (AGEs) in the development of arterial stiffening has been suggested. Advanced glycation end-products form by a nonenzymatic reaction between reducing sugars and biological proteins. Mechanisms underlying these alterations include AGE cross-linking of collagen and AGE interactions with circulating proteins and AGE receptors. New pharmacologic agents that prevent AGE formation, break cross-links, or block AGE receptors reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation, and improve endothelial function. These agents promise to reduce the risk of isolated systolic hypertension, diastolic dysfunction, diabetes and thus, heart failure.