Showing papers in "Letters in Drug Design & Discovery in 2010"

Synthesis and Urease Inhibitory Properties of Some New N 4 -Substituted 5-Nitroisatin-3-thiosemicarbazones

Abstract: 4 -substituted 5-nitroisatin-3-thiosemicarbazones 2a-2q has been synthesized and screened for in vitro urease inhibitory activities. Compounds 2a-2d, 2g, 2i, 2j and 2q were found to be potent inhibitors of the enzyme. Of these, 2c exhibited a potent inhibitory activity with IC50 value 16.4 � M and may act as a lead molecule for further studies. Structure-activity relationship studies revealed that electronic effects of the substituents play an important role in the urease inhibitory potential of the synthetic compounds. ery program (15-21), we have recently synthesized a number of N 4 - substituted isatin-3-thiosemicarbazones as urease inhibitors with non toxic nature (22, 23). These findings form a solid basis for further research on such compounds to develop more potent, safe and useful urease inhibitors. Furthermore, structure-activity rela- tionship (SAR) studies revealed that the type and position of the substituents on phenyl ring, substituted at N 4 of the thiosemicarba- zone moiety, play an important role in the urease inhibitory poten- tial of these compounds. To further enhance the activity of new antiurease compounds, the study of the combination of substitution at position-5 of the isatin scaffold with attachment of different aryl groups (having one or two substituents about the phenyl ring) at N 4 of the thiosemicarbazone moiety was considered worth pursuing. The present work therefore deals with the synthesis and evaluation of urease inhibitory potential of a series of seventeen N 4 - arylsubstituted 5-nitroisatin-3-thiosemicarbazones. We describe here the effects of the nature of aryl groups at N 4 (modified by placement of one or two substituents about the phenyl ring) and the presence of nitro function at position-5 of the isatin scaffold on the urease inhibitory potential of these compounds.

Synthesis and In Vitro Evaluation of Novel 1, 2, 4-Triazole Derivatives as Antifungal Agents

Abstract: Despite the advances in medicine and the emergence of new antifungal agents, fungal infections remain a significant cause of morbidity and mortality. Azoles are widely used as antifungal agents. Azoles interfere with the conversion of lanosterol to ergosterol by inhibiting a fungal cytochrome P450enzyme, lanosterol 14
-demethylase. Resistance to azoles, particularly fluconazole, is emerging to Candida albicans , after long-term suppressive therapy. Thus, there is an urgent need for newer potent antifungals to combat resistance developed against widely used azoles. In present work, we report synthesis of novel triazole derivatives of 7-hydroxy-4-methylcoumarin using various substituted aromatic aldehydes and evaluated for their in vitro fungicidal activity against Candida albicans at various con-centrations to obtain minimum inhibitory concentration (MIC). Keyword: Azole, Antifungal, Minimum inhibitory concentration, Coumarin, Triazole. INTRODUCTION Fungal infections remain a significant cause of morbidity and mortality despite advances in medicinal chemistry. Antifungal drug discovery has identified three classes of natural products (griseo-fulvin [1], polyenes [2] and echinocandins [3]) and four classes of synthetic chemicals (azoles [4], allylamines [5], flucytosine [6] and phenylmorpholines [7]) with clinical value against fungal infec-tions. The azoles class of antifungal agent is chemically either an imidazole or a triazole group joined to an asymmetric carbon atom as their functional pharmacophore. They all work by blocking the active site of an enzyme variously known as lanosterol 14
-demethylase or cytochrome P450

Application of Molecular Topology to the Search of Novel NSAIDs: Experimental Validation of Activity

Abstract: A topological-mathematical model obtained by linear discriminant analysis has been used to the search of new nonsteroidal antinflammatory drugs (NSAIDs). After carrying out an in silico screening based on such a model, on the Aldrich database, new structures potentially active were selected. Among these structures stand fourteen compounds, from which only one had been previously recorded as NSAID in the literature. The experimental tests performed on the remaining substances demonstrated that several compounds showed either in vitro or in vivo or both activity. Moreover, four compounds, namely 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea, 4,6-dichloro-2-methylthio-5-phenylpyrimidine, 2-chloro-2',6'-acetoxylidide and trans-1,3-diphenyl-2-propen-1-ol, showed a significant in vivo antinflammatory activity as compared to the reference drug (indomethacin). These results reinforce the role of Molecular Topology as a useful tool for drug discovery.

Making Drops in Microencapsulation Processes

Abstract: The present work is a review of classical and recently developed methods for drop production in micro- and nanoencapsulation processes. Most of the methods and technologies used in microencapsulation processes require the formation of drops as a previous step. The drop formation step is very influential for the subsequent microparticle size and size distribution. These parameters, together with the microparticle structure, usually determine the application. The most important methods and technologies used to generate drops are briefly described. These have been divided into three large groups as a function of their production rate and capacity for drop-size control. A comparative review is com- pleted, reporting the main advantages and disadvantages of the key technologies.

Synthesis and Antimicrobial Activity of N,N'-Bis(2-hydroxylbenzyl)-1,2-ethanediamine Derivatives.

Abstract: A series of N,N'-Bis(2-hydroxylbenzyl)-1,2-ethanediamine derivatives and its schiff bases were synthesized, characterized and screened for in vitro antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella enterica Result indicated that the ethylenediamine derivatives, N,N'-Bis(2-hydroxy-5-bromobenzyl)-1,2-ethanediamine (21), and N,N'-Bis(2-hydroxy-5-chlorobenzyl)-1,2-ethanediamine (22) showed the most favorable antimicrobial activity exhibiting LC(50) of 116 and 879 muM against Senterica, 86 and 138 muM against P aeruginosa, and 140 and 287 muM against S aureus, respectively These compounds displayed highest level of resistance with S aureus Thus, the high level of activity seen with the compounds (21, 22) suggests that these compounds could serve as the leads for development of novel synthetic compounds with enhanced antimicrobial activity

In Vitro Antiprotozoal Evaluation of Zinc and Copper Complexes Based on Sulfonamides Containing 8-Aminoquinoline Ligands

Abstract: The present paper reports the synthesis and antiprotozoal activity of N-quinolin-8-yl-arylsulfonamides and their copper and zinc complexes. Sulfonamides 2-5 were synthesized by reacting 8-aminoquinoline with several commercial arylsulfonyl chlorides. The corresponding complexes 6-13 were obtained using copper (II) acetate or zinc chloride in methanol. In vitro activity was carried out against promastigote forms of Leishmania braziliensis and L. chagasi, and epimastigote forms of Trypanosoma cruzi. Selected compounds were tested against axenic amastigote forms of L. braziliensis. The new 2,5-dichlorobenzenesulfonamide ligand was found to be inactive under the selected bioassays, however its copper complex 8 was active with the highest selective indexes (SI) against L. braziliensis promastigote and amastigote forms, with IC50 values of 2.59 and 0.35 μM, respectively. Difluorinated copper 10 and zinc 11 complexes were most active against L. braziliensis, with IC50 of 1.11 μM and 1.25 μM, respectively. However, the SI values were about 12 for both compounds. In general, the complexation of sulfonamides increases the antiprotozoal activity, as well as the cytotoxicity on Vero cells. These results confirm the antiprotozoal potential of sulfonamides and metal-based sulfonamides.

Synthesis and Antimycobacterial Activity of 2-aryl-3-(arylmethyl)-1,3-thiazolidin-4-ones

Abstract: Fifteen new heterocyclic thiazolidinones have been synthesized from one-pot reactions of piperonylamine, are- nealdehydes and mercaptoacetic acid. These compounds plus ten 2-aryl-3-(benzyl)-1,3-thiazolidin-4-ones which had been previously synthesized, were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Six of the series exhibited modest activity when compared to the first line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of multi-drug resistant tuberculosis.

Design, Synthesis and 3-D Characterization of 1-Benzenesulfonyl-1,2,3,4- Tetrahydroquinolines as Lead Scaffold for Antiparasitic Drug

Abstract: Ten 1-benzenesulfonyl-1,2,3,4-tetrahydroquinoline (BSTHQ) were synthesized and characterized and their antiprotozoal activities were investigated. This small library was designed by combining two chemical moieties that are known to be biologically active by itself. The BS group seems to be favorable for the antiparasitic activity, since the derivatives presented lower IC50 value than the precursor heterocycle. Most compounds were moderately active against T cruzi, but 3 showed a promising IC50 value (9.76 M) with low cytotoxicity (L6). Also, 3, 6 and 9 showed interesting activity and reasonable selectivity against P. falciparum. These derivatives are considered as lead scaffolds and merit further exploration through structure optimization.

Homology Modelling of Human E1 Ubiquitin Activating Enzyme

Abstract: Human E1 is a key player in protein ubiquitination, however the E1 structure is not available. In this paper, we describe the derivation of a human E1 structure using molecular modelling based on the crystal structure of S. cerevisiae E1 and M. Musculus E1. Key interactions between our E1 model and ubiquitin are also discussed.