Synthesis and biological evaluation of novel (L)-alpha-amino acid methyl ester, heteroalkyl, and aryl substituted 1,4-naphthoquinone derivatives as antifungal and antibacterial agents

A series of (S)-N-(1,4-naphthoquinon-2-yl)-alpha-amino acid methyl esters 3-9, 2-N,N-dialkylamino-1,4-naphthoquinones 10-11 and 2-hydroxy-3-(2'-mercaptoimidazolyl)-1,4-naphthoquinones and their cyclic analogs 12-15 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationships of these compounds were studied and the results show that the compounds 9b and 13c exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii, whereas compound 6a showed in vitro antibacterial activity against Streptococcus faecalis, K. pneumoniae, Escherichia coli, and Staphylococcus aureus.     

QSAR studies on structurally similar 2-(4-methanesulfonylphenyl)pyran-4-ones as selective COX-2 inhibitors: a Hansch approach

QSAR analysis based on classical Hansch approach was adopted on two recently reported novel series of 2-phenylpyran-4-ones as selective cyclooxygenase-2 (COX-2) inhibitors. The 6-methyl derivatives of title compounds bifurcate as 3-phenoxypyran-4-ones (subset A) and 3-phenylpyran-4-ones (subset B) among series 1. Series 2 consists of 5-chloro derivatives of title compounds. Various regression equations were derived to study the influence of phenoxy and phenyl ring substituents of series 1 compounds on COX-2, COX-1 and selective COX-2 over COX-1 inhibitory activity. The best triparametric equation derived for 36 compounds of series 1 explains the hydrophobic, electronic and steric requirements for improved COX-2 inhibitory activity. QSAR model derived to explore the selective COX-2 over COX-1 inhibition showed that selectivity could be influenced by size and lipophilicity of substituents. The size of the first atom of 2 substituents appears to have negative effect on selectivity, whereas highly polar 3 substituents at R are favorable for improved selectivity. QSAR investigations on series 2 compounds revealed some interesting correlation of COX-2 inhibitory activity with calculated physicochemical properties of whole molecules. The positive logP confirms the hydrophobic interaction of series 2 compounds with COX-2 enzyme. The positive MR term indicates that an overall increase in size and polarizabilty of the molecules increases COX-2 inhibitory activity. The positive contribution of structural variable suggests biphenyl analogs are extremely potent COX-2 inhibitors.     

An efficient synthesis of aryloxyphenyl cyclopropyl methanones: a new class of anti-mycobacterial agents

An efficient, high yield and one-pot synthesis of phenyl cyclopropyl methanones by reaction of different aryl alcohols with 4'-fluoro-4-chloro-butyrophenone in THF/DMF in the presence of NaH/TBAB is reported. Most of the methanones were further reduced to respective alcohols or methylenes. All the compounds were evaluated for their anti-tubercular activities against M. tuberculosis H37Rv in vitro displaying MICs ranging from 25 to 3.125 microg/mL. The most active compounds showed activity against MDR strains and two of them (14 and 16) showed marginal enhancement of MST in mice.     

Amide derivatives of 9,11-seco-estra-1,3,5(10)-trien-11-oic acid as modified orally active estrogen agonists with moderate antagonistic activity

Synthesis of amide derivatives of 9,11-seco-estra-1,3,5(10)-trien-11-oic acid containing alkyl and aromatic amine residues has been carried out with an aim to prepare orally active estrogen antagonists. Modification of the estradiol molecule in the form of C-seco-amide derivatives has led to their high oral absorption. Compounds 7 an n-propyl amide, 8 an n-butyl amide, and 16 a p-anisidyl amide of C-seco-estrane showed significant estrogen antagonistic activity (>20%), while, the majority of compounds possessed high estrogen agonistic activity on oral administration at 10mg/kg dose in rats.     

Unusual structural,functional, and stability properties of serine hydroxymethyltransferase from Mycobacterium tuberculosis

From the genome analysis of the Mycobacterium tuberculosis two putative genes namely GlyA and GlyA2 have been proposed to encode for the enzyme serine hydroxymethyltransferase. We have cloned, overexpressed, and purified to homogeneity their respective protein products, serine hydroxymethyltransferase, SHM1 and SHM2. The recombinant SHM1 and SHM2 exist as homodimers of molecular mass about 90 kDa under physiological conditions, however, SHM2 has more compact conformation and higher thermal stability than SHM1. The most interesting structural observation was that the SHM1 contains 1 mol of pyridoxal 5'-phosphate (PLP)/mol of enzyme dimer. This is the first report of such a unique stoichiometry of PLP and enzyme dimer for SHMT. The SHM2 contains 2 mol of PLP/mol of enzyme dimer, which is the usual stoichiometry reported for SHMT. Functionally both the recombinant enzymes showed catalysis of reversible interconversion of serine and glycine and aldol cleavage of a 3-hydroxyamino acid. However, unlike SHMT from other sources both SHM1 and SHM2 do not undergo half-transamination reaction with d-alanine resulting in formation of apoenzyme but l-cysteine removed the prosthetic group, PLP, from both the recombinant enzymes leaving the respective inactive apoenzymes. Comparative structural studies on the two enzymes showed that the SHM1 is resistant to alkaline denaturation up to pH 10.5, whereas the native SHM2 dimer dissociates into monomer at pH 9. Urea- and guanidinium chloride-induced two-step unfolding of SHM1 and SHM2 with the first step being dissociation of dimer into apomonomer at low denaturant concentrations followed by unfolding of the stabilized monomer at higher denaturant concentrations.     

Oxalate selectively activates p38 mitogen-activated protein kinase and c-Jun N-terminal kinase signal transduction pathways in renal epithelial cells

Oxalate, a metabolic end product, is an important factor in the pathogenesis of renal stone disease. Oxalate exposure to renal epithelial cells results in re-initiation of the DNA synthesis, altered gene expression, and apoptosis, but the signaling pathways involved in these diverse effects have not been evaluated. The effects of oxalate on mitogen- and stress-activated protein kinase signaling pathways were studied in LLC-PK1 cells. Exposure to oxalate (1 mM) rapidly stimulated robust phosphorylation and activation of p38 MAPK. Oxalate exposure also induced modest activation of JNK, as monitored by phosphorylation of c-Jun. In contrast, oxalate exposure had no effect on phosphorylation and enzyme activity of p42/44 MAPK. We also show that specific inhibition of p38 MAPK by 4(4-(fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)imidazole (SB203580) or by overexpression of a kinase-dead dominant negative mutant of p38 MAPK abolishes oxalate induced re-initiation of DNA synthesis in LLC-PK1 cells. The inhibition is dose-dependent and correlates with in situ activity of native p38 MAP kinase, determined as MAPK-activated protein kinase-2 activity in cell extracts. Thus, this study not only provides the first demonstration of selective activation of p38 MAPK and JNK signaling pathways by oxalate but also suggests that p38 MAPK activity is essential for the effects of oxalate on re-initiation of DNA synthesis.     

In vitro control of fasciation in proliferating nucellar embryos of Mangifera indica L. var totapari red small for cloning

Nucellar tissue contained in ovular halves of young fruits of Mangifera indica L. totapari red small, a dwarfing rootstock, differentiated fasciated embryonal structures in presence of 6-benzylaminopurine [BAP(0.15 mg l(-1))], 6-(gamma-gamma-dimethylallylamino) purine [2iP(0.15 mg l(-1))] and indole-3-acetic acid [(IAA(0.5 mg l(-1))] incorporated in the semisolid medium during 50-60 days. Due to embryonal fasciation, hardly 2-3 well-formed embryos could be obtained per culture of proliferating embryos. Of the 3 ethylene inhibitors [L-alpha-(2-aminoethoxyvinyl)-glycine-HCl (AVG), AgNO3 and salicylic acid (SA)] used, embryonal fasciation and necrosis of intervening tissue was completely controlled by 3-4 subcultures of fasciated mass of embryos under the influence of AVG (0.05 mg l(-1)) in presence of adenine sulphate [AdS (50 mg l(-1))] incorporated in the same medium. Almost synchronized development of isolated embryos, measuring ca 2 cm in length, was observed in a different medium used in liquid stationary state and supplemented, particularly with stress-producing substances [abscisic acid (ABA, 0.01 mg l(-1)); and polyethylene glycol (PEG, 100 mg l(-1))] besides certain other modifications. About 34% convertibility of processed embryos was obtained during a period of 90 days. The plantlets had well-developed roots along with laterals which were longer than leafy shoots. In vitro raised plants survived ex vitro for about 2 months.