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Abstract: Herein we present the synthesis of several new hydrazino derivatives of cyclopenta[c]pyridine, 5,6,7,8-tetrahydroisoquinoline and pyrano[3,4-c]pyridine from 3-oxo-4-cyano fused pyridine derivatives. The hydrazino derivatives obtained were used as starting materials for the synthesis of isomeric triazolopyrimidines as well as tetrazolopyrimidines. Furthermore, the rearrangement of triazolopyrimidines 7 into triazolopyrimidines 8 is also presented. In DMSO tetrazolopyrimidines 10 were shown to be in equilibrium with the relevant azidopyrimidines 9. The tetrazolopyrimidine structure was confirmed by X-ray crystallography. The synthesized compounds were tested for their antimicrobial activity. [Copyright &y& Elsevier]

Abstract: A new series of S,N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S,N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis. [Copyright &y& Elsevier]

Abstract: Balanced modulation of several targets is one of the current strategies for the treatment of multi-factorial diseases. Based on the knowledge of inflammation mechanisms, it was inferred that the balanced inhibition of cyclooxygenase-1/cyclooxygenase-2/lipoxygenase might be a promising approach for treatment of such a multifactorial disease state as inflammation. Detection of fragments responsible for interaction with enzyme’s binding site provides the basis for designing new molecules with increased affinity and selectivity. A new chemoinformatics approach was proposed and applied to create a fragment library that was used to design novel inhibitors of cycloxygenase-1/cycloxygenase-2/lipoxygenase enzymes. Potential binding sites were elucidated by docking. Synthesis of novel compounds, and the in vitro/in vivo biological testing confirmed the results of computational studies. The benzothiazolyl moiety was proved to be of great significance for developing more potent inhibitors. [Copyright &y& Elsevier]

Abstract: New (E)-1-(4-methyl-2-(alkylamino)thiazol-5-yl)-3-arylprop-2-en-1-ones, unsubstituted or carrying fluoro, bromo, methoxy, nitro, methyl and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and fungi. The compounds were very potent towards all tested microorganisms and in most cases their activity was better than that of reference drugs. [Copyright &y& Elsevier]

Abstract: As part of ongoing studies in developing new antimicrobials, we report the synthesis of a new class of structurally novel derivatives, that incorporate two known bioactive structures a thiazole and chalcone, to yield a class of compounds with interesting antimicrobial properties. Evaluation of antibacterial activity showed that almost all the compounds exhibited greater activity than reference drugs and thus could be promising novel drug candidates. [Copyright &y& Elsevier]

Abstract: As part of ongoing studies in developing new antimicrobials, a class of structurally novel 4-thiazolidinone derivatives incorporating three known bioactive nuclei such as thiazole, thiazolidinone and adamantane was synthesized by the multi-step reaction protocol, already reported in the literature. NMR and Molecular Modeling techniques were employed for structure elucidation and Z/E potential isomerism configuration of the analogues. Evaluation of antibacterial and antifungal activity showed that almost all compounds exhibited better results than reference drugs thus they could be promising candidates for novel drugs. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 2-Heteroarylimino-5-benzylidene-4-thiazolidinones, unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesised and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The antimicrobial activity of the 2-benzo[d]thiazolyl- and of the 2-benzo[d]isothiazolyl-imino-5-benzylidene-4-thiazolidinones is, on the whole, lower in comparison with the high activity detected for the derivatives of the 2-thiazolylimino-5-benzylidene-4-thiazolidinone class. Nevertheless most of the benzo[d]thiazole analogues display good inhibition of the growth of Gram positive bacilli and staphylococci, including methicillin-resistant Staphylococcus strains. Among the 2-benzo[d]isothiazole analogues a few derivatives show a strong and selective activity against bacilli. Moreover, it is worth noting that the replacement of the thiazole nucleus for the benzo[d]thiazole bicyclic system in the parent 2-(benzo[d]thiazol-2-ylimino)thiazolidin-4-one leads to significant antifungal properties against both yeasts and moulds, properties not shown by the analogous 2-thiazolyl- and 2-benzo[d]isothiazolyl-imino)thiazolidin-4-ones. The structure-activity relationship of 33 analogues possessing the 2-heteroarylimino-4-thiazolidinone structure is analysed through QSAR models. [Copyright &y& Elsevier]

Abstract: To assess the relative toxicity of the herbicides acetochlor and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) on the nervous system, the sciatic nerve of the frog (Rana ridibunda) nerve was incubated in saline inside a specially designed recording chamber. This chamber permits monitoring of the evoked compound action potential (CAP) of the nerve, a parameter that could be used to quantify the vitality of the nerve in normal conditions as well as when the nerve was exposed to the compounds under investigation. Thus, when the nerve was exposed to acetochlor, the EC50 was estimated to be 0.22mM, while for 2,4,5-T the EC50 was 0.90mM. Using the identical nerve preparation, the EC50 of 2,4-D was estimated to be 3.80mM [Kouri, G., Theophilidis, G., 2002. The action of the herbicide 2,4-dichlorophenoxyacetic acid on the isolated sciatic nerve of the frog (Rana ridibunda). Neurotoxicol. Res. 4, 25–32]. The ratio of the relative toxicity for acetochlor, 2,4,5-T and 2,4-D was found to be 1:4:17.2. However, because it is well-known that the action of 2,4-D is dependent on the pH, the relative toxicity of the three compounds was tested at pH 3.3, since it has been found that the sciatic nerve of the frog is tolerant of such a low pH. Under these conditions, the EC50 was 0.77mM (from 0.22mM at pH 7.2) for acetochlor, 0.20mM (from 0.90mM) for 2,4,5-T and 0.24mM (from 3.80mM at pH 7.2) for 2,4-D. Thus, the relative toxicity of the three compounds changed drastically to 1:0.25:0.31. This change in the relative toxicity is due not only to the increase in the toxicity of 2,4,5-T and 2,4-D at low pH levels, but also to the decrease in the toxicity of acetochlor at pH 3.3. [Copyright &y& Elsevier]

Abstract: New 2-thiazolylimino-5-arylidene-4-thiazolidinones (compounds 4a–j), unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The compounds were very potent towards all tested Gram positive microorganisms (MIC ranging from 0.03 to 6μg/mL in most of the cases) and Gram negative Haemophilus influenzae (MIC 0.15–1.5μg/mL), whereas no effectiveness was exhibited against Gram negative Escherichia coli and fungi up to the concentration of 100μg/mL. The 5-arylidene derivatives showed an antibacterial efficacy considerably greater than that of the parent 2-(thiazol-2-ylimino)thiazolidin-4-one 3, suggesting that the substituted and unsubstituted 5-arylidene moiety plays an important role in enhancing the antimicrobial properties of this class of compounds. The remarkable inhibition of the growth of penicillin-resistant staphylococci makes these substances promising agents also for the treatment of infections caused by microorganisms resistant to currently available drugs. [Copyright &y& Elsevier]

Abstract: A series of thiazolyl-N-phenyl piperazines has been synthesised and tested for anti-inflammatory activity. Their R M values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and logPsk also performed. The effect of the synthesised compounds on inflammation, using the carrageenin induced mouse paw oedema model was studied. In general, the studied compounds were found to be potent anti-inflammatory agents (44–74.1%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesised compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure–activity relationship approach (QSAR). [Copyright &y& Elsevier]

Three new series of benzo[d]isothiazole, benzothiazole and thiazole Schiff bases were synthesized and tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhoea) or against drug-resistant cancers (leukaemia, carcinoma, melanoma, MDR tumors) for which no definitive cure or efficacious vaccine is available at present. In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA+ viruses Yellow fever virus (YFV) and Bovine viral diarrhoea virus (BVDV), both belonging to Flaviviridae. Title compounds were also tested against representatives of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Salmonella spp.), various atypic mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis), yeast (Candida albicans) and mould (Aspergillus fumigatus). None of the compounds showed antiviral or antimicrobial activity. The benzo[d]isothiazole compounds showed a marked cytotoxicity (CC50=4–9 μM) against the human CD4+ lymphocytes (MT-4) that were used to support HIV-1 growth. For this reason, the most cytotoxic compounds of this series were evaluated for their antiproliferative activity against a panel of human cell lines derived from haematological and solid tumors. The results highlighted that all the benzo[d]isothiazole derivatives inhibited the growth of leukaemia cell lines, whereas only one of the above mentioned compounds (1e) showed antiproliferative activity against two solid tumor-derived cell lines. [Copyright &y& Elsevier]

A series of 2-dialkylamino-N-(4-substituted thiazolyl-2)acetamides and 3-dialkylamino-N-(4-substituted thiazolyl-2)propionamides were synthesized and evaluated for their anti-inflammatory activity. Encouraging results led us to investigate the effect of these compounds on NO production and GAGs release. Their effects were evaluated in vitro on the metabolism of pig cartilage, treated with IL-1β. The amount of glycosaminoglycans (GAGs) and the production of nitric oxide (NO) in the culture medium were determined. The results, obtained, showed that all compounds, in the presence of IL-1β, blocked the cartilage breakdown, with different behavior. A quantitative structure–activity relationship (QSAR) study was performed. [Copyright &y& Elsevier]

In continuation of our previous research, several new thiazolyl/thiazolinyl/benzothiazolyl Schiff bases have been designed, synthesized and identified. The referred compounds are reported to act as lipoxygenase inhibitors affecting inflammation and/or psoriasis. The compounds were screened for their reducing activity (with the stable free radical 1,1-diphenyl-2-picryl-hydrazyl, DPPH) and for inhibition of soybean lipoxygenase (LOX). Anti-inflammatory activity was examined in vivo using the carrageenin induced mice paw edema (32.6–75%). The results are discussed in terms of structural and physicochemical characteristics of the compounds. Compound 2d possessed the highest inhibition 75%. [Copyright &y& Elsevier]

Herein we report the design, synthesis, molecular docking study and evaluation of antimicrobial activity of ten new dithioloquinolinethiones. The structures of compounds were confirmed by 1H NMR, 13C NMR and HPLC-HRMS. Before evaluation of their possible antimicrobial activity prediction of toxicity was performed. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. All compounds appeared to be more active than ampicillin and almost all than streptomycin. The best antibacterial activity was observed for compound 8c 4,4,8-trimethyl-5-{[(4-phenyl-5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)thio]acetyl}-4,5-dihydro-1H-[1,2]dithiolo[3,4c]quino lone-1-thione). The most sensitive bacterium En.cloacae followed by S. aureus , while L.monocytogenes was the most resistant. All compounds were tested for antifungal activity also against eight fungal species. The best activity was expressed by compound 8d (5-[(4,5-Dihydro-1,3-thiazol-2-ylthio)acetyl]-4,4-dimethyl-4,5-dihydro-1H-[1,2]dithiolo[3,4-c]quinoline-1-thione). The most sensitive fungal was T. viride , while P. verrucosum var. cyclopium was the most resistant one. All compounds were more potent as antifungal agent than reference compound bifonazole and ketoconazole. The docking studies indicated a probable involvement of E. coli DNA GyrB inhibition in the anti-bacterial mechanism, while CYP51ca inhibition is probably responsible for antifungal activity of tested compounds. It is interesting to mention that docking results coincides with experimental. Ten dithioloquinolinethiones were synthesized and evaluated for their antimicrobial activity. Docking studies were performed also. Image 1 • Antimicrobial and antifungal activities of novel steroids. • Molecular docking studies on E.coli MurB enzyme. • Molecular docking studies on C.albicans lanosterol 14alpha-demethylase (CYP51). [ABSTRACT FROM AUTHOR]

Starting from 7(8)-chlorofuro(thieno)[3,2- d ]pyrimidines 1 , the corresponding 7(8)-hydrazinofuro(thieno)[3,2- d ]pyrimidines 2 were obtained by reaction with hydrazine. By treatment with nitrous acid, compounds 2 gave fused furo- and thieno[2,3- e ]tetrazolo[1,5- c ]pyrimidines 3 T and 4 T in excellent yields, which in solution exist in equilibrium with 7(8)-azidofuro(thieno)[3,2- d ]pyrimidines 3 A and 4 A . Compounds 3 T / 3 A and 4 T / 4 A represent useful substrates for investigating the azide/tetrazole equilibrium: it has been examined as a function of solvent, temperature, and their structure. We have observed that, in solution, in both 3 and 4 the equilibrium was strongly affected by the solvent used. In contrast, X-ray analysis has shown that both thieno[2,3- e ]tetrazolo[1,5- c ]pyrimidines and furo[2,3- e ]tetrazolo[1,5- c ]pyrimidines in solid state exist only in the tetrazole tautomeric form. For this reason the equilibrium constants and the relevant thermodynamic parameters have been calculated in different solvents: finally excellent logarithmic plots of Δ G ° values versus dielectric constants have been observed (slopes 10.00÷10.57; correlation coefficients 0.9962÷0.9999) for a series (seven examples) of furo compounds 3 . [ABSTRACT FROM AUTHOR]

Ethyl 1-aminofuro(thieno)[2,3- b ]pyridine-2-carboxylates 1 reacted with benzoyl isothiocyanate and gave the relevant thioureido derivatives 2 , whose intramolecular cyclization under the action of potassium hydroxide furnished the relevant 9(10)-thioxopyrido[3′,2′:4,5]furo(thieno)[3,2- d ]pyrimidin-7(8)-ones 3 . Compounds 3 with methyl iodide could give the S -methyl 4 and S , N -dimethyl 5 derivatives. Interestingly 3 by alkylation with alkyl dichlorides (bifunctional reagents) the cyclization to a thiazoline or to a thiazine ring on the [ a ] side of the pyrimidine ring occurs, with formation of the new pentacyclic systems: furo(thieno)[3,2- d ][1,3]thiazolo[3,2- a ]pyrimidin-7(8)-ones 6 and furo(thieno)[3′,2′:4,5]pyrimido[2,1- b ][1,3]thiazin-7(8)-ones 7 . Moreover compounds 3 by alkylation with p -chlorophenacyl bromide (again a bifunctional reagent) led to the formation of the corresponding S -alkylated compounds 9 , whose cyclization furnished structural analogues of compounds 6 : p -chlorophenyl-substituted thiazolo[3,2- a ]pyrimidin-7(8)-ones 10 . The structure of the obtained compounds has been unambiguously confirmed by using a wide spectrum of physico-chemical methods and, in the instance of compounds 6 and 7 , also by an alternative synthesis via a double-annelation reaction using a BMMA reagent. Biological tests have shown promising antimicrobial activity against Staphylococcus aureus for some of the synthesized compounds. [ABSTRACT FROM AUTHOR]

The treatment of 2-[(1-alkyl(aryl)-4-cyano-5,6,7,8-tetrahydroisoquinolin-3-yl)oxy]acetamides ( 5 ) with sodium ethoxide to induce a cyclization to form 5-alkyl(aryl)-1-amino-6,7,8,9-tetrahydrofuro[2,3- c ]isoquinoline-2-carboxamides 4 furnished unexpected results. Compounds 5 gave rise to two different processes: the expected formation of compounds 4 and the unexpected formation of 1-alkyl(aryl)-3-amino-4-cyano-5,6,7,8-tetrahydroisoquinolines 6 (via a Smiles-like rearrangement). The characteristics of this rearrangement have been thoroughly investigated as a function of the structure of the starting 5 . Moreover, by exploiting this rearrangement, 2-(5,6,7,8-tetrahydroisoquinolin-3-yl)oxy]acetohydrazides 7 gave new pyrazolo[3,4- b ]pyridines 8 . Thus, this rearrangement represents a new method for the synthesis of 6 and 8 , compounds interesting from a biological point of view. All of the examined reactions occur with good-excellent yields, ranging between 78 and 88%. [ABSTRACT FROM AUTHOR]

By exploiting the reactivity of 7-alkyl-3-chloro-4-cyano-1-hydrazino-5,6,7,8-tetrahydro-2,7-naphthyridines 5 some 7-alkyl-1-azido-3-chloro-4-cyano-5,6,7,8-tetrahydro-2,7-naphthyridines 6 were synthesized. Looking at their chemical properties we have ascertained that in these compounds the azide/tetrazole equilibrium is completely shifted towards the azido form (both in solid state and in solution). Their behaviour with some amines was tested as well. Moreover by exploiting the reactivity of the chlorine and of the nitrile group we have fused on the pyridine system two new rings (pyrazole or thiophene), thus obtaining previously unknown heterocyclic systems ( 10 and 11 ). Interestingly, in these new systems, the position of the above equilibrium is reversed. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

A series of derivatives of a new heterocyclic system, pyrido[3′,2′:4,5]furo[3,2- d ][1,2,4]triazolo[4,3- a ]pyrimidin-7(8)-one 5 , was synthesized starting from the ethyl 1-aminofuro[2,3- b ]pyridine-2-carboxylates 1 . By alkylation with methyl iodide compounds 5 afforded 11(12)-methylpyrido[3′,2′:4,5]furo[3,2- d ][1,2,4]triazolo[4,3- a ]pyrimidin-7(8)-ones 6 . The structure of the obtained compounds besides the spectroscopic methods was confirmed by X-ray analysis. [ABSTRACT FROM AUTHOR]

Abstract: A series of substituted arylidene thiazoles were allowed to react with Wittig–Horner (WH) reagent, tetraethyl methyl-1,1-bisphosphonate, to produce via Michael addition reaction the corresponding heteroarylmethylenebisphosphonates (BPs) in different yields according to the experimental conditions. Acid hydrolysis of the new BPs was undertaken to obtain the corresponding bisphosphonic acids. Prediction and the in vivo activity of the products in the rat adjuvant model are also discussed in terms of structure–activity relationships (SAR). [Copyright &y& Elsevier]

A series of anti-inflammatory agents known as Schiff bases, combining thiazolyl and benzothiazolyl ring and vanillin moieties in the same molecule, was synthesized and evaluated for screening anti-degenerative activity on nasal pig cartilage cultures treated with interleukin 1β (IL-1β). The amount of glycosaminoglycans (GAGs), the production of nitric oxide (NO) and prostaglandin E2 (PGE2), released into the culture medium, were detected. The tested Schiff bases decreased, dose-dependently, the NO and PGE2 production and the GAGs release with respect to samples treated with IL-1β alone, showing a different behavior correlated to their structure. These results suggest that thiazolyl and benzothiazolyl Schiff bases in general, and particularly the Schiff base with bromine and methoxyl group in position three would protect cartilage matrix from degenerative factors induced by IL-1β. [Copyright &y& Elsevier]

Graphical abstract Fourteen steroid compounds were in silico evaluated using computer program PASS as antimicrobial agents. The experimental studies evaluation revealed that all compounds have good antibacterial activity with MIC at range of 0.003–0.96 mg/mL and MBC 0.06–1.92 mg/mL. Docking studies were performed on several antimicrobial and antifungal targets. Highlights • Antimicrobial and antifungal activities of novel steroids. • Molecular docking studies on E. coli MurB enzyme. • Molecular docking studies on C. albicans lanosterol 14alpha-demethylase (CYP51). Abstract Fourteen steroid compounds were in silico evaluated using computer program PASS as antimicrobial agents. The experimental studies evaluation revealed that all compounds have good antibacterial activity with MIC at range of 0.003–0.96 mg/mL and MBC 0.06–1.92 mg/mL. Almost all compounds except of compound 4 (3β-acetoxy-1/- p -chlorophenyl-3/-methyl-5α-androstano[17,16- d ]pyrazoline) were more potent than Ampicillin, and they were equipotent or more potent than Streptomycine. All compounds exhibited good antifungal activity with MIC at 0.003–0.96 mg/mL and MFC at 0.006–1.92 mg/mL but with different sensitivity against fungi tested. According to docking studies 14-alpha demethylase inhibition may be responsible for antifungal activity. Prediction of toxicity by PROTOX and GUSAR revealed that compounds have low toxicity and can be considered as potential lead compounds for the further studies. [ABSTRACT FROM AUTHOR]

In continuation of our efforts to develop new compounds with antimicrobial properties we describe design, synthesis, molecular docking study and evaluation of antimicrobial activity of seventeen novel 2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-arylidene-1,3-thiazolidin-4-ones. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. Twelve out of seventeen compounds were more potent than streptomycin and all compounds exhibited higher potency than ampicillin. Compounds were also tested against three resistant bacterial strains: MRSA, P. aeruginosa and E. coli . The best antibacterial potential against ATCC and resistant strains was observed for compound 8 (2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-(4-nitrobenzylidene)-1,3thiazolidin-4-one). The most sensitive bacterium appeared to be S. typhimirium , followed by B. cereus while L. monocitogenes and M. flavus were the most resistant. Compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited antifungal activity better than the reference drugs bifonazole and ketokonazole (3-115 times). It was found that compound 8 appeared again to be the most potent. Molecular docking studies on E. coli MurB, MurA as well as C. albicans CYP 51 and dihydrofolate reductase were used for the prediction of mechanism of antibacterial and antifungal activities confirming the experimental results. [ABSTRACT FROM AUTHOR]

A novel series of compounds containing a polar, non-flat 2-imidazoline core was designed based on the SAR information available for aromatic azole cyclooxygenase-2 inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300 nM) comparable to clinically used Celecoxib and was shown to be more selective. The series represents the first example of selective COX-2 inhibitors built around a distinctly polar core, contradicting an earlier accepted view that a lipophilic scaffold is required for high inhibitor potency. The lead compound demonstrated very good oral bioavailability in mice, slow metabolic degradation, modest distribution into the brain and a remarkable anti-inflammatory efficacy in carrageenan-induced mouse paw edema model. A foundation has therefore been laid for a chemically novel series of COX-2 inhibitors that has a potential for diverse therapeutic applications in inflammatory disease area. [ABSTRACT FROM AUTHOR]

Abstract: The reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine 1 with nucleophiles has been investigated. The different reactivity of the two chlorine atoms in 1 enabled us to obtain, by using different experimental conditions, the mono- and the di-amino-substituted derivatives of 5,6,7,8-tetrahydro-2,7-naphthyridines 2 and 3, respectively. Thus, by carrying out the reaction in a low-boiling solvent and in the presence of a quasi-stoichiometric amount of amine, the mono-substituted derivatives 2 were obtained, which under harsher conditions was transformed into the diamino derivatives 3 when using an excess of amine. During the synthesis of some diamino derivatives 3 a new rearrangement was observed with formation of 1-oxo derivatives of 3,4-dihydro-2,7-naphthyridines 4. The structure of the unexpected compounds 4 was confirmed by X-ray crystallography. A mechanism for the rearrangement is tentatively suggested. [Copyright &y& Elsevier]

Abstract: A series of 82 5-aryl-2-thio-1,3,4-oxadiazole derivatives were screened for their anti-mycobacterial activities against Mycobacterium tuberculosis H37Rv. The synthesized compounds 30–37 appeared to be the most active derivatives exhibiting more than 90% inhibition of mycobacterial growth at 12.5μg/mL. Structure–activity relationships study was performed for the given series by using the electronic-topological method combined with neural networks (ETM–NN). A system for the anti-mycobacterial activity prediction was developed as the result of training associative neural network (ASNN) with weights calculated from projections of a compound and each pharmacophoric fragment found on the elements of the Kohonen’s self-organizing maps (SOMs). From the detailed analysis of all compounds under study, the necessary requirements for a compound to possess antituberculosis activity have been formulated. The analysis has shown that any requirement’s violation for a molecule implies a considerable decrease or even complete loss of its activity. Molecular docking studies of the compounds allowed shedding light on the binding mode of these novel anti-mycobacterial inhibitors. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Cyclisation of pyrazolo-β-enaminones 3 readily obtained from 4-aceto acetyl pyrazol 2 with triphosgene led to the formation of N-substituted pyrazolo-1,3-oxazin-2-ones 4 in good yields. Estimation of pharmacotherapeutic potential, possible molecule mechanisms of action, toxic/side effects and interaction with drug-metabolizing enzymes were made for synthesised compounds on the basis of prediction of activity spectra for substances (PASS) prediction results and their analysis by PharmaExpert software. COX inhibition predicted by PASS was confirmed by experimental evaluation. [Copyright &y& Elsevier]

Abstract: N-acetyl-l-cysteine (NAC), at a concentration of 1–60mM, has been previously used extensively for protection in a variety of cell cultures against the deleterious effects of various compounds. The results of this in vitro study show that NAC has certain unusual effects on the evoked compound action potential (CAP) of the rat sciatic nerve fibers. Firstly, at concentrations of 5.0, 3.5 and 2.5mM, concentrations used by others as a protectant for cell cultures, NAC inhibits the action potentials of the sciatic nerve fibers completely in a concentration-dependent manner within a few minutes or hours (2.5mM). Secondly, the acute inhibitory action of NAC on the CAP of the nerve fibers was not spontaneously reversible, but as soon as NAC was replaced with saline there was a partial (∼75%) recovery in the function of the nerve fibers. Thirdly, the no observed effect concentration for NAC was estimated to be 1mM. The paradox is that NAC at 1mM not only had no effect on the nerve fibers, but it became an excellent neuroprotective compound, giving almost 100% neuroprotection against cadmium-induced neurotoxicity. The results show a possible effect of NAC on voltage-gated sodium and potassium channels. The observed neuroprotective-neurotoxic properties of NAC require careful reconsideration of its use in either in vitro studies or in vivo pharmaceutical applications. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: The effects on nerve tissue of three dental impression pastes were compared in this study. Two of the impression pastes, Examix and Express 3M, contained vinyl polysiloxane while the other, Xanthopren, did not. An in vitro model based on the isolated sciatic nerve of the frog and rat was used. As an indication of the proper functioning of the fibres in the nerve, the amplitude of evoked compound action potential (CAP) was monitored continuously. The results clearly showed that the number of active nerve fibres in the isolated sciatic nerves of either rat or frog exposed directly to impression pastes containing vinyl polysiloxane, decreased much faster than those of the nerves in contact to impression material without vinyl polysiloxane. When the nerve of the frog was exposed to Xanthopren there was a decrease in the CAP to 50% of the control values within 56.87±2.42h (n =6). This value was called inhibition time to 50%, IT50 and for Examix it was found to be 9.97±1.53h. When the nerve of the rat was exposed to Xanthopren, the IT50 was 15.34±2.97h (n =6) for the Xanthopren and only 2.86±1.20h for Examix and 2.76±0.48h for Express 3M (n =6). There was no significant difference between the action of the last two compounds (P =0.85). This fast nerve fibre inactivation could be caused either by the chemical used for the synthesis of the two impression pastes, Examix and Express 3M, or by the unusual constriction of the nerve when it is embedded in the materials with vinyl polysiloxane. There is strong evidence to support the first case, since the incubation of the nerve in the presence of Examix, Express 3M and Xantopren in a way so the nerve was not in contact with the impression pastes, shows a much faster decrease of the CAP in the presence of the first two pastes. The decrease is caused by the death of nerve fibres, since there is no recovery in the CAP after the removal of Examix from the incubating saline. [Copyright &y& Elsevier]

The search for new antimicrobial agents is greater than ever due to the perpetual threat of multidrug resistance in known pathogens and the relentless emergence of new infections. In this manuscript, ten thiazole-based thiazolidinone hybrids bearing a 6-trifluoromethoxy substituent on the benzothiazole core were synthesized and evaluated against a panel of four bacterial strains Salmonella typhimurium, Staphylococcus aureus, Escherichia coli and Listeria monocytogenes and three resistant strains Pseudomonas aeruginosa , E. coli and MRSA. The evaluation of minimum bactericidal and minimum inhibitory concentrations was accomplished by microdilution assay. As reference compounds ampicillin and streptomycin were employed. All compounds displayed antibacterial efficiencies with MBCs/MICs at 0.25–1 mg/mL and 0.12–1 mg/mL respectively while ampicillin displayed MBCs/MICs at 0.15–0.3 mg/mL and at 0.1–0.2 mg/mL respectively. MICs/MBC of streptomycin varied from 0.05 to 0.15 mg/mL and from 0.1 to 0.3 mg/mL respectively. The best overall effect was observed for compound h4, while compound h1 exhibited the highest effective action against E. coli (MIC/MBC 0.12/0.25 mg/ml) among all tested compounds. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a metabolic disease characterized by high blood glucose levels and usually associated with several chronic pathologies. Aldose reductase and protein tyrosine phosphatase 1B enzymes have identified as two novel molecular targets associated with the onset and progression of type II diabetes and related comorbidities. Although many inhibitors against these enzymes have already found in the field of diabetic mellitus, the research for discovering more effective and selective agents with optimal pharmacokinetic properties continues. In addition, dual inhibition of these target proteins has proved as a promising therapeutic approach. A variety of diverse scaffolds are presented in this review for the future design of potent and selective inhibitors of aldose reductase and protein tyrosine phosphatase 1B based on the most important structural features of both enzymes. The discovery of novel dual aldose reductase and protein tyrosine phosphatase 1B inhibitors could be effective therapeutic molecules for the treatment of insulin-resistant type II diabetes mellitus. The methods used comprise a literature survey and X-ray crystal structures derived from Protein Databank (PDB). Despite the available therapeutic options for type II diabetes mellitus, the inhibitors of aldose reductase and protein tyrosine phosphatase 1B could be two promising approaches for the effective treatment of hyperglycemia and diabetes-associated pathologies. Due to the poor pharmacokinetic profile and low in vivo efficacy of existing inhibitors of both targets, the research turned to more selective and cell-permeable agents as well as multi-target molecules. [ABSTRACT FROM AUTHOR]

1,2,4-Triazole is a very important scaffold in medicinal chemistry due to the wide spectrum of biological activities and mainly antifungal activity of 1,2,4-triazole derivatives. The main mechanism of antifungal action of the latter is inhibition of 14-alpha-demethylase enzyme (CYP51). The current study presents synthesis and evaluation of eight triazole derivatives for their antimicrobial activity. Docking studies to elucidate the mechanism of action were also performed. The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method. All tested compounds showed good antibacterial activity with MIC and MBC values ranging from 0.0002 to 0.0069 mM. Compound 2 h appeared to be the most active among all tested with MIC at 0.0002–0.0033 mM and MBC at 0.0004–0.0033 mM followed by compounds 2f and 2g. The most sensitive bacterium appeared to be Xanthomonas campestris while Erwinia amylovora was the most resistant. The evaluation of antifungal activity revealed that all compounds showed good antifungal activity with MIC values ranging from 0.02 mM to 0.52 mM and MFC from 0.03 mM to 0.52 mM better than reference drugs ketoconazole (MIC and MFC values at 0.28–1.88 mM and 0.38 mM to 2.82 mM respectively) and bifonazole (MIC and MFC values at 0.32–0.64 mM and 0.64–0.81 mM). The best antifungal activity is displayed by compound 2 h with MIC at 0.02–0.04 mM and MFC at 0.03–0.06 mM while compound 2a showed the lowest activity. The results showed that these compounds could be lead compounds in search for new potent antimicrobial agents. Docking studies confirmed experimental results. [ABSTRACT FROM AUTHOR]

A number of compounds targeting different processes of the Human Immunodeficiency Virus type 1 (HIV-1) life cycle have been developed in the continuing fight against AIDS. Coumarin-based molecules already proved to act as HIV-1 Protease (PR) or Integrase (IN) inhibitors and also to target HIV-1 reverse transcriptase (RT), blocking the DNA-dependent DNA-polymerase activity or the RNA-dependent DNA-polymerase activity working as common NNRTIs. In the present study, with the aim to exploit a coumarin-based scaffold to achieve the inhibition of multiple viral coded enzymatic functions, novel 4-hydroxy-2 H , 5H-pyrano (3, 2-c) chromene–2, 5–dione derivatives were synthesized. The modeling studies calculated the theoretical binding affinity of the synthesized compounds on both HIV-1 IN and RT-associated Ribonuclease H (RNase H) active sites, which was confirmed by biological assays. Our results provide a basis for the identification of dual HIV-1 IN and RT RNase H inhibitors compounds. Image 1 • Dual inhibitors are a new approach in the anti-HIV therapy. • 16 4-hydroxypyranobenzopyran derivatives were synthesized as dual inhibitors. • They showed anti-HIV activity in the low micromolar range. • Modeling studies were applied on both HIV-1 IN and RT RNase H active site. • Compound 7 was the most promising HIV-1 IN and RT RNase H dual inhibitor. [ABSTRACT FROM AUTHOR]