Balekudru Devadas

Bio: Balekudru Devadas is an academic researcher from G. D. Searle & Company. The author has contributed to research in topics: Candida albicans & Proteases. The author has an hindex of 13, co-authored 18 publications receiving 794 citations.

Substituted benzopyran derivatives for the treatment of inflammation

Abstract: A class of benzopyran derivatives is described for use in treating cyclooxygenase-2 mediated disorders. Compounds of particular interest are defined by Formula (I'), wherein X, A?1, A2, A3, A4?, R, R', R?1 and R2? are as described in the specification.

Substituted benzopyran analogs for the treatment of inflammation

Abstract: A class of benzopyrans, benzothiopyrans, dihydroquinolines, dihydronaphthalenes, and analogs thereof, is described for use in treating cyclooxygenase-2 mediated disorders. Compounds of particular interest are defined by Formula (I') wherein X, A?1, A2, A3, A4?, R, R'', R?1 and R2? are as described in the specification.

Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors

Abstract: This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating disorders mediated by cyclooxygenase-2 or 5-lipoxygenase, such as inflammation.

Design and synthesis of novel imidazole-substituted dipeptide amides as potent and selective inhibitors of Candida albicans myristoylCoA:protein N-myristoyltransferase and identification of related tripeptide inhibitors with mechanism-based antifungal activity.

Abstract: A new class of antifungal agents has been discovered which exert their activity by blockade of myristoylCoA: protein N-myristoyltransferase (NMT; EC 2.1.3.97). Genetic experiments have established that NMT is needed to maintain the viability of Candida albicans and Cryptococcus neoformans,the two principal causes of systemic fungal infections in immunocompromised humans. Beginning with a weak octapeptide inhibitor ALYASKLS-NH2 (2, Ki = 15.3 +/- 6.4 microM), a series of imidazole-substituted Ser-Lys dipeptide amides have been designed and synthesized as potent and selective inhibitors of Candida albicans NMT. The strategy that led to these inhibitors evolved from the identification of those functional groups in the high-affinity octapeptide substrate GLYASKLS-NH2 1a necessary for tight binding, truncation of the C-terminus, replacement of the four amino acids at the N-terminus by a spacer group, and substitution of the glycine amino group with an N-linked 2-methylimidazole moiety. Initial structure-activity studies led to the identification of 31 as a potent and selective peptidomimetic inhibitor with an IC50 of 56 nM and 250-fold selectivity versus human NMT. 2-Methylimidazole as the N-terminal amine replacement in combination with a 4-substituted phenacetyl moiety imparts remarkable potency and selectivity to this novel class of inhibitors. The (S,S) stereochemistry of serine and lysine residues is critical for the inhibitory activity, since the (R,R) enantiomer 40 is 10(3)-fold less active than the (S,S) isomer 31. The inhibitory profile exhibited by this new class of NMT ligands is a function of the pKa of the imidazole substituent as illustrated by the benzimidazole analog 35 which is about 10-fold less potent than 31. The measured pKa (7.1 +/- 0.5) of 2-methylimidazole in 31 is comparable with the estimated pKa (approximately 8.0) of the glycyl residue in the high-affinity substrate 1a. Groups bulkier than methyl, such as ethyl, isopropyl, or iodo, at the imidazole 2-position have a detrimental effect on potency. Further refinement of 31 by grafting an alpha-methyl group at the benzylic position adjacent to the serine residue led to 61 with an IC50 of 40 nM. Subsequent chiral chromatography of 61 culminated in the discovery of the most potent Candida NMT inhibitor 61a reported to date with an IC50 of 20 nM and 400-fold selectivity versus the human enzyme. Both 31 and 61a are competitive inhibitors of Candida NMT with respect to the octapeptide substrate GNAASARR-NH2 with Ki(app) = 30 and 27 nM, respectively. The potency and selectivity displayed by these inhibitors are dependent upon the size and orientation of the alpha-substituent. An alpha-methyl group with the R configuration corresponding to the (S)-methyl-4-alanine in 2 confers maximum potency and selectivity. Structural modification of 31 and 61 by appending an (S)-carboxyl group beta to the cyclohexyl moiety provided the less potent tripeptide inhibitors 73a and 73b with an IC50 of 1.45 +/- 0.08 and 0.38 +/- 0.03 microM, respectively. However, these tripeptides (73a and 73b) exhibited a pronounced selectivity of 560- and 2200-fold versus the human NMT. More importantly 73a displayed fungistatic activity against C albicans with an EC50 of 51 +/- 17 microM in cell culture. Compound 73b also exhibited a similar antifungal activity. An Arf protein gel mobility shift assay for monitoring intracellular myristoylation revealed that a single dose of 200 microM of 73a or 73b produced 1000 microM against C. albicans NMT did not exhibit antifungal activity and produced no detectable reduction in Arf N-myristoylation in cultures of C. albicans. These studies confirm that the observed antifungal activity of 73a and 73b is due to the attenuation of NMT activity and that NMT represents an attractive tar

9 Biology and enzymology of protein N-myristoylation

Abstract: Publisher Summary This chapter reviews a number of studies that have advanced the understanding of how proteins are N-myristoylated and how N-myristoyl proteins function. Thermodynamic analyses of the interactions of acyl peptides and acyl proteins with model membranes have confirmed the importance of the limited hydrophobicity of myristate in regulating dynamic interactions between N-myristoyl proteins and their membrane or protein partners. Genetic studies have shown that protein N-myristoylation is essential for the survival of Saccharomyces cerevisiae during periods when nutrients are unlimited, as well as during periods when nutrients are scarce. Genetic studies have also shown that protein N-myristoylation is required for the survival of the common human fungal pathogens Candida albicans and Cryptococcus neoformans . Analyses of the enzyme responsible for catalyzing protein N-myristoylation—myristoyl-CoA, protein N-myristoyltransferase (Nmt)—have disclosed that orthologous Nmts have subtle differences in their peptide substrate specificities and that these differences can be exploited to generate species-selective inhibitors of fungal Nmts that are fungicidal. X-Ray crystallographic determination of the structure of Nmt has revealed how this enzyme interacts with its substrates, and how catalysis occurs through a novel mechanism.

Substituted isoxazoles for the treatment of inflammation

Abstract: A class of substituted isoxazolyl compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula (III) whrein R7 is selected from hydroxyl, lower alkyl, carboxyl, halo, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxyalkyl, lower carboxyalkoxyalkyl, lower haloalkyl, lower haloalkylsulfonyloxy, lower hydroxylalkyl, lower aryl (hydroxylalkyl), lower carboxyaryloxyalkyl, lower alkoxycarbonylaryloxyalkyl, lower cycloalkyl, lower cycloalkylalkyl, and lower aralkyl; and wherein R8 is one or more radicals independently selected from hydrido, lower alkylsulfinyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, lower arylamino, lower aminoalkyl, nitro, halo, lower alkoxy, aminosulfonyl, and lower alkylthio; or a pharmaceutically-acceptable salt thereof.