Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme

Megazol (7) is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8) in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR) enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7) for nitrogen (in the triazole in 8), the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7.

Synthesis and biological evaluation of some benzimidazo-1,2,4-triazole derivatives as antimicrobial and anti-inflammatory agents

Three new series of N-[aryl or heteroarylmethylidene]-2-[1H-1,2,4-triazolo[2,3-a] benzimidazol-2-ylsuljanyl] acetohydrazides [4a-k], N-[alpha-arylethylidene]-2-[1H-1, 2, 4-triazolo[2,3-aJbenzimidazol-2-ylsuljanyl] acetohydrazides [5a-d], and 2-[[[5-[alkyl or aralkylsulfanyl]-1, 3, 4-oxadiazol-2-yl]methyl]sulfanyl]-1 H-1, 2, 4-triazolo[2,3-alpha] benzimidazoles [7a-e] were synthesized. Reaction of compound [1] with methyl bromoacetate afforded [2], which when refluxed with hydrazine hydrate yielded [3]. The latter was condensed with aromatic aldehydes and substituted acetophenones to afford compounds [4a-k] and [5a-d] respectively. Treatment of compound [3] with carbon disulfide in the presence of potassium hydroxide resulted in the formation of [6]. The latter was alkylated with the appropriate alkyl or aralkyl halides to afford compounds [7a-e]. The purity of all new compounds was checked by TLC and elucidation of their structures was confirmed by IR, [1]HNMR, and mass spectrometry along with elemental microanalyses. All the target compounds were evaluated for their in-vitro antimicrobial and in-vivo anti-inflammatory activities in comparison with ampicillin, fluconazole, and indomethacin as reference drugs respectively. In addition to molecular docking of compound 5c was performed

Assessment of the stability of novel antibacterial triazolyl oxazolidinones using a stability-indicating high-performance liquid chromatography method

To evaluate the stability of 12 triazolyl oxazolidinone [TOZ] derivatives in simulated gastric and intestinal fluids as well as in human plasma at 37 +/- 1°C. A stability-indicating high-performance liquid chromatography [HPLC] procedure with a C8 column [250 +/- 40 mm, 5 micro m particle size] and a mobile phase of acetonitrile/H2O [50/50 v/v] at 1.0 ml/min was used. Accelerated stability studies were conducted at 37 +/- 1°C in 0.1 M HCl solution as simulated gastric fluid and in phosphate buffer solution [pH about 7.4] as simulated intestinal fluid. The stability of TOZs in human plasma at a simulated biological temperature of 37 +/- 1°C was evaluated as well. The stability studies indicated that the examined TOZs were stable in the above media, with the exception of compounds 1a [tert- butyl 4-[4-[[R]-5-[[1H-1,2,3-triazol-1-yl]methyl]-2-oxooxazolidin-3-yl]-2-fluorophenyl]piperazine-1-carboxylate] and 1b [tert-butyl 4-[2-fluoro-4-[[R]-5-[[4-methyl-1H-1,2,3-triazol- 1-yl]methyl]-2-oxooxazolidin-3-yl]phenyl] piperazine-1-carboxylate], which underwent degradation in simulated gastric fluid. The degradation kinetics revealed degradation parameters [kdeg, t1/2, t90] of 0.180 h-1, 3.85 h, and 0.58 h for 1a and of 0.184 h-1, 3.76 h and 0.57 h for 1b, respectively. Furthermore, the degradation products were identified by mass-spectrometric analysis at mass-to-charge ratios 347.5 and 361.5, respectively, and proton nuclear magnetic resonance analysis. With the exception of compounds 1a and 1b, the TOZs are stable in simulated gastric and intestinal fluids as well as in human plasma. Being carbamate derivatives, compounds 1a and 1b underwent fast and complete degradation in simulated gastric fluid. The obtained results should be considered for future studies of formulation of structurally related TOZs in oral dosage forms

Homology modeling and QSAR analysis of 1,3,4-thiadiazole and 1,3,4-triazole derivatives as carbonic anhydrase inhibitors.

Carbonic anhydrase (CA) inhibitors are very interesting target for designing anticancer (hypoxic) and antiglaucoma drugs. In the present study, a 3D homology modeling of human carbonic anhydrase-IX (hCA-IX) isozyme, based upon the crystal structure of murine CA-XIVA (PDB CODE 1RJ5) was performed, as no experimental 3D structures are available. A homology model of hCA-IX was developed and validated. To explore the responsible physicochemical properties of 1,3,4-thiadiazole and 1,3,4-triazole derivatives for carbonic anhydrase inhibition, a quantitative structure activity relationship (QSAR) study was performed having hCA-II and hCA-IX inhibitory activity respectively. In hCA-II and hCA-IX inhibitory activities, four significant models with good correlations ( 0.945 & 0.926) were obtained; two models (models 1 and 3) were selected based on statistical criterion. The QSAR study revealed that in case of hCA-II, overall increase in size and volume of molecule, introduction of electropositive surfaces might increase the inhibitory activity, whereas in case of hCA-IX, decreasing the hydrophobicity and introduction of electron releasing substituents might increase the hCA-IX inhibitory activity.

Deferasirox: Oral, once daily iron chelator - An expert opinion.

Iron overload is a serious and potentially fatal condition that results from multiple blood transfusions required over a long period of time to treat certain types of anemias such as, that caused by β-thalassemia, sickle cell disease and myelodysplastic syndrome. Deferoxamine, which has been used since four decades as an iron chelator has limited efficacy due to its demanding therapeutic regimen, leading to poor compliance. Deferasirox, once daily oral iron chelator provides an effective alternative to Deferoxamine in the treatment of transfusional hemosiderosis. In this review, the role of Deferasirox as an ideal iron chelator has been discussed. Pubmed searches on Deferasirox were carried out for the same. Several studies demonstrated the safety and efficacy of Deferasirox in reducing iron burden in iron-overloaded patients with β-thalassemia, sickle cell anemia and myelodysplastic anemia. Thus, convenient, effective and tolerable chelation therapy with oral Deferasirox is likely to be a significant development in the treatment of transfusional iron overload, due to its ability to provide constant chelation coverage and the potential to improve compliance.

Design, synthesis and molecular modeling study of 1,2,4-triazole carbohydrazide derivatives with potential antimicrobial and anti-inflammatory activities

The present investigation is concerned with the synthesis of 1,2,4-triazole carbohydrazide derivatives [6a-I] with the objective of discovering novel and potent antimicrobial and anti-inflammatory agents. The chemical structures of the target compounds were elucidated by elemental analyses, IR, [1]H-NMR, [13]C-NMR and mass spectral data. The antimicrobial activity of the target compounds were evaluated and compared with ampicillin trihydrate and clotrimazole as references compounds. The results showed that compound 6i revealed a similiar level of activity as ampicillin against Staphylococcus aureus, while compounds 6j and 6l exhibited comparable activity against Escherichia coli. All compounds were less active against Candida albicans when compared with clotrimazole. The results of anti-inflammatory showed that compounds 6d, 6l possessed higher anti-inflammatory activity than celecoxib in carageenan-induced rat paw edema test with low gastric ulcerogenicity compared with indomethacin. Molecular modeling studies were performed in order to rationalize the obtained biological results

Treatment of invasive fungal infections: stability of voriconazole infusion solutions in PVC bags

Voriconazole is a novel broad-spectrum antifungal drug, employed in the treatment of invasive fungal infections, and represents an alternative to amphotericin B treatment. The manufacturer recommends that any unused reconstituted product should be stored at 2ºC to 8ºC, for no more than 24 h, but no recommendations about i.v. infusion solutions are given. Previous works have reported on the stability of voriconazole in polyolefin bags and just one in 5 percent dextrose polyvinyl chloride (PVC) bags, at a 4 mg.mL-1 concentration. In this work, the stability of voriconazole as an i.v. infusion solution in 0.9 percent sodium chloride and in 5 percent dextrose, in PVC bags, at 0.5 mg.mL-1, stored at 4 ºC and at room temperature, protected from light, was evaluated. These infusion solutions were analyzed for a 21-day period. Chemical stability was evaluated by HPLC assay. Visual inspection was performed and pH of the solutions was measured. No color change or precipitation in the solutions was observed. The drug content remained above 90 percent for 11 days in 0.9 percent sodium chloride and for 9 days in 5 percent dextrose solutions. The i.v. infusion solutions stored at room temperature were not stable. At room temperature, the voriconazole content dropped down to 88.3 and 86.6 percent, in 0.9 percent sodium chloride or 5 percent dextrose solutions, respectively, two days after admixture. Assays performed at the end of the study suggest the sorption of voriconazole by the PVC bags. The results of this study allow cost-effective batch production in the hospital pharmacy.

Abnormal anther development and high sporopollenin synthesis in benzotriazole treated male sterile Helianthus annuus L.

Foliar application of 1.5% benzotriazole induced 100% pollen sterility in H. annuus. Pollen abortion in treated plants was mainly associated with abnormal behaviour of tapetum. A limited number of anther locule showed early degeneration of tapetum followed by disintegration of sporogenous tissues. On the other hand, some locules showed normal development of tapetum at initial stages. However, this tapetum exhibited degenerated and non-functional cell organelles. In both these situations tapetum failed to provide proper nourishment to developing microspores. The ultrastructure of both tapetum and microspores is different from that of control material with irregularities of exine deposition, endopolyploidy of tapetal nuclei and an alteration of organelle composition being correlated with sterility. Pollen grains thus developed were devoid of nucleus and cell organelles and were complete sterile.

1-Azido-4-Phenyl-1,4-Butanedione as a convenient precursor for the synthesis of various nitrogen heterocycles

1 -AZIDO-4-phenyl-1,4-butanedione 2 proved to be a convenient precursor for the synthesis of a variety of heterocyclic systems through its treatment with some acidic and basic reagents. For example, 2-benzazepine-1,5-dione 3, 1,3-oxazolane-2,4-dione 4a, 1,3-thiazolane-2,4-dione 4b, 1,3-oxazol-5-one 5, quinazoline-2,4-dione 7, 4,6-diaryl-2-pyrimidineones 9a-d, 2,5-bis-substituted amino-1,3,4-oxadiazole II,5-aryl-2-N-substituted amino-1,3,4-oxadiazoles 13a,b, 1,2,4-triazol-3-ones 14a,b, 1,3-benzoxazine-2,4 [3H]-dione 15 and 1,3,4-oxadiazol-2[3H]-ones 16a,b

Synthesis of some thiazolidinone and triazole dderivatives of expected antimicrobial activity

New derivatives of semicarbazide [5] and thiosemicarbazide [6] had been synthesized together with new substituted alkyl and aryl 1, 2, 4-triazoles [7] and thiazolidinone [8] obtained by cyclizing the appropriate thiosemicarbazide [6]. Screening for antibacterial and antifungal activities using preliminary scan by the agar plate inhibition zone method, followed by MIC versus ampicillin and clotrimazole revealed high activity for compounds [5-c] and [7-a]. The partition coefficient of the most and least biologically active compounds was determined and the results were reported

A theoretical study of hydrophobic fragment and factor constants of Hansch and Leo: estimation of a few non-available fragments and factors.

Hydrophobic fragment constants (f) of benzotriazol-2-yl and Ar-N[CO-]2 systems, and aliphatic H/S polar interaction factors F(H/S) in Cl2CHCONH-Ar and Cl3CCONH-Ar, of Hansch and Leo's constructionist approach, were estimated as 0.69 (standard deviation = 0.17), -1.98, 0.95 and 0.98 respectively. The validity of the first constant has been tested by calculating the log P of compounds not included in the regression.

Metal complexes of triazole-2-yl thiourea: synthesis, characterization and equilibrium studies

Triazoles have been reported to be biologically versatile compounds, having bactericidal[1], fungicidal [2] insecticidal[3] and pesticidal[4]properties, also thiourea. Frequently display a wide biocidal activities [5,6]. It is well known that certain metal complexes have greater activity than the coordinating agents themselves [7] This has led us to study in the present work a new thiourea derivative having a triazole moiety with some transition metal ions, in continuation to previous studies on thiourea complexes[8]. The present investigation comprises l-triazole-2-yl-3-benzoyl- thiourea, BTu, and some of its metal complexes. The composition and structure of the formed complexes have been characterized by elemental analysis, potentiometric titrations, electrolyte conductance, IR, electronic and proton NMR spectrometry and magnetic susceptibility measurements

Analise quimico-farmaceutica do terconazol / Chemical pharmaceutical analysis of the terconazol

O terconazol e respectivas formas farmaceuticas de creme e ovulos foram analizados por metodos fisicos, fisico-quimicos e quimicos. Fizeram-se testes de caracterizacao como faixa de fusao, analise elementar, perda por dessecacao, solubilidade, rotacao especifica, residuo por incineracao e analise termica. Realizaram-se provas de identificacao cromatografica, espectrometrica e quimica funcional. Efetuaram-se determinacoes quantitativas em meio nao aquoso, metodo de Schoniger, espectrometria no UV, no visivel com ion ferrico e cromatografia liquida de alta eficiencia

Spectroscopic studies of some schiff bases derived from indole and aniline derivatives or diamino Triazole with benzaldehyde derivatives

The electronic absorption spectra of the Schiff bases derived from indole and aniline derivatives or diaminotriazole with benzaldehyde derivatives were investigated in organic solvents of varying polarities. The important bands in IR-spectra of the compounds, as well as the main signals in 1H-NMR spectra were assigned and discussed in relation to molecular structure

Terconazol: nova arma antifúngica / Terconazole: new antifungal weapon

As doenças causadas por fungos têm ocorrido com maior freqüência, nos últimos anos, devido a mudanças de hábitos das pessoas, principalmente a liberaçäo sexual. Na tentativa de resolver este desafio terapêutico, os pesquisadores passaram a desenvolver novos antifúngicos. Dentre estes, surgiu o terconazol, primeiro membro da nova classe de compostos triazólicos. É muito eficaz em sua açäo tópica, possui amplo espectro, constituindo-se em fármaco de primeira escolha no tratamento de várias micoses