Synthesis of Highly Functionalized Spirobutenolides via a Nitroalkane-Mediated Ring Contraction of 2-Oxobenzo[ h]chromenes through Denitration.

A facile synthesis of highly functionalized spirobutenolides was carried out by a nitroalkane carbanion-induced ring opening and relactonization via a denitration reaction of 2-oxo-5,6-dihydro-2 H-benzo[ h]chromene-3-carbonitriles and 2-oxo-2,5-dihydrothiochromeno[4,3- b]pyran-3-carbonitriles. However, when nitroethane was used as a nucleophile source in lieu of nitromethane, a mixture of ( E)- and ( Z)-isomers of the corresponding spirobutenolides was obtained in a different ratio. The structure and geometry of the product were confirmed by single-crystal X-ray diffraction. The isolated ( E)- and ( Z)-butenolides with the treatment with sodium ethoxide in DMF at room temperature provided highly substituted trienes via an allylic ring opening followed by decarboxylation.

Synthesis of 1-amino-2-aroyl/acetylnaphthalenes through a base mediated one pot inter and intramolecular C-C bond formation strategy.

A new precursor 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile has been synthesized by the reaction of 2-cyanomethylbenzonitrile, carbon disulfide and methyl iodide under basic conditions. The reaction of 2-(1-cyano-2,2-bis(methylthio)vinyl)benzonitrile with various functionalized aryl/heteroaryl methyl ketones or acetone under basic conditions afforded 4-amino-3-aroyl/heteroaroyl/acetyl-2-methylsulfanylnaphthalene-1-carbonitriles in good yields through a (5C + 1C) annulation strategy; this involves sequential intermolecular, followed by intramolecular, C-C bond formation reactions. The structure of the product was confirmed by single crystal X-ray crystallography.

Regioselective synthesis of polycyclic aza-oxa and aza-oxa-thia heteroarenes as Colo-205 and HepG2 carcinoma cells growth inhibitors.

An efficient regioselective synthesis of polycyclic diheteroaryl[b,d]pyrans and diheteroaryl[c,e][1,2]diazepines has been reported through ring transformation reactions of 2-oxo-2,5-dihydrothiochromeno[4,3-b]pyrans (3,4), 2-oxo-5,6-dihydro-2H-benzo[b]pyrano[2,3-d]oxepine/thiepine (8, 9) and 6-oxo-3,6-dihydro-2H-naphtho[1,2-b]pyrano[2,3-d]oxepine (15) by hydrazine, at ambient and reflux temperature. Nine compounds viz 5a,b; 10a,c,d; 12b; 13b; 16 and 1-methylthio-5,6-dihydrobenzo[f]quinoline (0.1-100 µM) were screened for their cytotoxicity in normal (IEC-6), carcinoma (Colo-205) and HepG2 cell lines. None of the compounds showed cytotoxicity in normal IEC-6 cells while 10a,d and 16 resulted in killing of Colo-205 cells with IC50 ranging 20-60 µM while 10c and 13b caused killing of HepG2 cells with IC50 values ranging 60-80 µM concentration. Further, 10a,d and 16 caused apoptosis through a cascade of mitochondrial pathway in Colo-205 cells indicating anticancerous potential against intestinal cancer. Interestingly, compounds 10c and 13b exhibited apoptosis through mitochondrial pathway in HepG2 cells suggesting anticancer activity against hepatic cancer.

Direct alkenylation of indolin-2-ones by 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles: a novel approach.

A direct one-pot base-induced alkenylation of indolin-2-ones has been developed by using 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles. Different bases such as MeONa, NaH and t-BuONa have been used to optimize the reaction conditions to obtain the desired product. NaH in THF was found to be the most suitable for the alkenylation of indolin-2-ones. Reaction in the presence of other bases led to the formation of 1-aryl-3-methoxy/methylthio-5H-dibenzo[d,f][1,3]diazepin-6(7H)-ones. Quantum chemical calculations have been performed to explain the nature of the weak noncovalent interactions operating in the supramolecular architectures of alkenylated indoline-2-ones and to explain the relative stability of one of the tautomers with respect to the others.

Sequential approach to the synthesis of 'U and Z' shaped polycyclic heteroarenes.

The synthesis of three new classes of heteroarenes, built through the sequential fusion of naphthalene, benzo/naphtho[b]oxepine and thiochromene rings with pyran and pyrimidine ring systems to give 'U and Z' shaped structural frameworks is reported. The methodology is based on the synthesis of pyran fused intermediates, 1-methylthio-3-oxo-5,6-dihydro-3H-benzo[f]chromene-2-carbonitrile (3), 4-methylthio-2-oxo-5,6-dihydro-2H-benzo/naphtho[b]pyrano[2,3-d]oxepine-3-carbonitriles (10, 20) and 4-methylthio-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles (15) from the reaction of 2-tetralone, benzo/naphtho[b]oxepin-5-ones and thiochromen-4-ones with methyl 2-cyano-3,3-dimethylthioacrylate respectively. Further condensation of intermediates 3, 10, 20 and 15 with amidines led to the formation of tetracyclic 'U' shaped 4-amino-2-aryl-7,8-dihydro-5-oxo-5H-naphtho[2,1-b]pyrimido[4,5-d]pyrans (8) and 'Z' shaped 4-amino-2-aryl-5-oxo-12,13-dihydro-5H-benzo/naphtho[b]oxepino[5,4-b]pyrimido[4,5-d]pyrans (12, 22) and 4-amino-2-aryl-5-oxo-5,12-dihydrothiochromeno[4,3-b]pyrimido[4,5-d]pyrans (17). Compound 12f forms a chain of dimers through N-HO interactions as indicated by the X-ray structure analysis, and the quantum chemical calculations performed at the MP2 level indicate that this interaction energy is 10 kJ mol(-1).

Non-catalytic approach to the synthesis of partially reduced 'S' shaped dioxathia- and oxadithiahelicenes through base induced inter- and intramolecular C-C bond formation.

An efficient and convenient route for the construction of helical 'S' shaped dioxathia- and oxadithiahelicenes with oxygen and sulfur atoms located in the middle of the outer helix has been developed through base induced inter- and intramolecular C-C bond formation from the reaction of 4-sec-amino-2-oxo-2,5-dihydrothiochromeno[4,3-b]pyran-3-carbonitriles with 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-ones, 3,4-dihydrobenzo[b]thiepin-5(2H)-one and thiochroman-4-ones separately. Quantum chemical calculations have also been carried out to explore the geometries and electronic structures of newly synthesized compounds to envisage the pathway for interconversion of both atropisomers. The determination of helicity parameters and configurational stability demonstrate that the energy barrier is strongly dependent on the nature of hetero-atoms present.

An efficient de novo synthesis of partially reduced phenanthrenes through C-C insertion.

An efficient and novel approach to the synthesis of highly congested 3-alkyl-, 4-alkyl-, 3-aryl-, 3,4-dialkyl-, 4-alkyl-3-aryl-, and 3,4-diaryl-9,10-dihydro-1-sec-aminophenanthrene-2-carbonitriles has been delineated through the base-catalyzed ring transformation of 5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carbonitrile by carbanion derived in situ from various ketones in moderate to good yields. 9,10-Dihydrophenanthrenes with and without substituent in the bay region are efficiently and regioselectively synthesized by using propanal and acetyltrimethylsilane as a source of carbanion. Even the synthesis of bisphenanthrenes has been achieved by the ring transformation of 5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carbonitrile by 2-acetylphenanthrene in moderate yield. Highly substituted 3-amino-1-sec-amino-5,6-dihydrophenanthrene-2,4-dicarbonitriles have also been prepared from the reaction of 2-oxobenzo[h]chromene and malononitrile.

6-Aryl-4-methylsulfanyl-2H-pyran-2-one-3-carbonitriles as PPAR-gamma activators.

Various 6-aryl-3-cyano/methoxycarbonyl-4-methylsulfanyl-2H-pyran-2-ones have been synthesized as a potential substitute of 2,4-thiazolidinedione head group to express potent PPAR-gamma transactivation response. Some of the screened compounds have shown promising PPAR-gamma agonistic activity.

Synthesis and in vivo antihyperglycemic activity of 5-(1H-pyrazol-3-yl)methyl-1H-tetrazoles.

A series of 5-[(5-aryl-1H-pyrazol-3-yl)methyl]-1H-tetrazoles 3a-h have been synthesized and evaluated for their in vivo antihyperglycemic activity. Some of the synthesized compounds have shown significant glucose lowering activity in male Sprague-Dawley rats in sucrose loaded model. These compounds were also evaluated for their peroxisome proliferator activated receptor gamma agonistic property, but none of them displayed any significant activity.

Biaryls and heterobiaryls as alpha-glucosidase and protein tyrosine phosphatase inhibitors.

Various 6-aryl-4-substituted-2H-pyran-2-one-3-carbonitriles (1a-d) have been synthesized as precursor for the synthesis of 3,4-dihydro-1H-isothiochroman (2a) and benzocycloalkanes (2b-e). Highly functionalized 9-thiaphenanthrene (3b) and phenanthrene (3a) have also been obtained from the reaction of 1c with thiochroman-4-one and 1-tetralone separately. Similarly 4 has been obtained by the ring transformation of 1d by 4-trifluoromethylacetophenone. Most of the synthesized compounds were evaluated for alpha-glucosidase and protein tyrosine phosphatase inhibitory activities. Some of the compounds, 2a, 3a and b and 4 displayed better alpha-glucosidase inhibitory activity compared to standard drug acarbose.

Advances in molecular targets and chemotherapy of tuberculosis.

The need for newer, effective drugs with different modes of action against tuberculosis is great, despite the numerous drugs in clinical use and the development of Bacilli Calmette-Guerin (BCG) vaccine. Three major goals should be considered in the development of new antituberculosis drugs: 1) they should be fast acting to reduce the long duration of treatment, thereby avoiding drug toxicity; 2) they should be active against both sensitive and resistant strains of tubercle bacilli; and 3) they should possess significant activity against dormant bacilli, which represent the stage affecting one-third of the world's tuberculosis patients. This review provides an overview of important current drugs, novel targets for the development of antituberculosis agents and future drug candidates.

Synthesis and glucose-6-phosphatase inhibitory activity of (thiouriedo)alkanoic acid esters.

A series of (3-pyridin-2-yl-thiouriedo)alkanoic acid esters (5a-j) have been synthesized by the reaction of pyridin-2-yl-dithiocarbamic acid methyl ester (2) and amino acid esters (4). Most of the synthesized compounds have been evaluated against glucose-6-phosphatase enzyme but only four compounds (5g-j) displayed significant inhibitory activity of the enzyme.

Synthesis of bicyclic biaryls as glucose-6-phosphatase inhibitors.

Biaryls, 7-naphthyl-5-s-amino-2,3-dihydrobenzo[b]thiophene-4-carbonitriles (3a-e), 8-(1-naphthyl)-6-s-amino-isothiochroman-5-carbonitriles (6a-d), 4-(1-naphthyl)-2-s-aminobezocycloalkene-1-carbonitriles (6e-j), 8-naphthyl-6-s-amino-2-ethyl-1,2,3,4-tetrahydro-isoquinoline-5-carbonitrle (6k-n), 1-naphthyl-3-s-amino-10H-9-thia-phenantherene-4-carbonitriles (8a-e) and 1-(1-naphthyl)-3-s-amino-9,10-dihydrophenantherene-4-carbonitriles (8f-i) have been prepared through carbanion induced ring transformation reactions of 6-naphthyl-3-cyano-4-s-amino-2H-pyran-2-ones (1) from respective ketones (2, 5, and 7). These compounds have been evaluated for their glucose-6-phosphatase inhibitory activity and only 6a, c, j, m, c, d, h displayed significant inhibition of the glucose-6-phosphatase.

Therapeutic significance of peroxisome proliferator-activated receptor modulators in diabetes.

Peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, identified and encoded by different genes: PPARalpha, PPARdelta and PPARgamma. Each subtype of PPAR appears to be differently expressed in a tissue-specific manner due to its binding to a specific consensus DNA sequence of peroxisome proliferator response elements (PPREs). PPARalpha plays a significant role in the regulation of nutrient metabolism, including fatty acid oxidation, gluconeogenesis and amino acid metabolism. PPARdelta is expressed ubiquitously and has been found to be effective in controlling dyslipidemia and cardiovascular diseases, while PPARgamma isotype is mainly expressed in adipose tissue where it stimulates adipogenesis and lipogenesis. Thus PPARs have emerged as potential molecular targets for the design and synthesis of a different class of compounds, considering the conformation of receptors for the treatment of human metabolic disorders. This review concerns the therapeutic importance of PPARs in diabetes drug development.

Therapeutic role of peroxisome proliferator-activated receptors in obesity, diabetes and inflammation.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and play a significant role in regulation of lipid metabolism, hepatic peroxisomal enzyme expression, insulin sensitivity and glucose homeostasis. PPARs have been classified into three subtypes encoded by different genes: PPARalpha (NR1C1), PPARdelta (NR1C2), and PPARgamma (NR1C3). Each subtype of PPARs appears to be differently expressed in a tissue-specific manner because of their binding to specific consensus DNA sequences, known as PPREs (peroxisome proliferator response elements). Thus, PPARs have emerged as potential molecular targets for the design and synthesis of a different class of compounds, considering the conformation of receptors for the treatment of human metabolic disorders. This review covers the rapid progress made in functional analysis of PPARs and progress made towards the identification of ligands for each subtype receptor.

Synthesis and antihyperglycemic activity of suitably functionalized 3H-quinazolin-4-ones.

A series of 2-sec-amino-3H-quinazolin-4-ones (4a-p) and 4-sec-amino-2-chloroquinazolines (5a-b) have been synthesized by nucleophilic substitution reaction of 2-chloro-4(3H)-quinazolones (3) and 2,4-dichloroquinazolines (2) with amines, respectively. Most of the synthesized compounds were evaluated for antihyperglycemic activity but only 4a,b,d,j,o displayed significant reduction in blood glucose level in streptozotocin and sucrose loaded rat models.

Synthesis of aminonicotinonitriles and diaminopyridines through base-catalyzed ring transformation of 2H-pyran-2-ones.

An efficient and convenient synthesis of 2-amino-6-aryl-4-methylsulfanylnicotinonitriles (2), 2-amino-6-aryl-4-substituted-aminonicotinonitriles (4), and 2-amino-6-aryl-4-substituted-aminopyridines (6) has been delineated and illustrated through base-catalyzed ring transformation of 6-aryl-3-cyano-4-methylsulfanyl/substituted-amino-2H-pyran-2-ones (1, 3, and 5) with cyanamide and ammonium carbonate separately.

Hepatoprotection by 3-bromo-6-(4-chlorophenyl)-4-methylthio-2H-pyran-2-one against experimentally induced liver injury in rats.

Hepatoprotective activity of 3-bromo-6-(4-chlorophenyl)-4-methylthio-2H-pyran-2-one, an isostere of dimethyl ricinine, was evaluated in adult male albino rats intoxicated with carbon tetrachloride, paracetamol or thioacetamide. The test compound showed significant hepatoprotection at 6.0 mg kg(-1) body mass daily dose, given to the rats for seven consecutive days. The carbon tetrachloride, paracetamol and thioacetamide were given, respectively, on days 3, 5, and 7, on day 6 and on day 6 post treatment with the test compound. The protective effect was evident in a battery of serum and liver biochemical parameters related to hepatotoxicity.

Visceral Leishmaniasis: Clinical Features, Pathology, Diagnosis and Chemotherapeutic Developments.

Visceral leishmaniasis, or kala-azar, is a chronic disease caused by Leishmania donovani, Leishmania chagasi or Leishmania infantum. The disease is transmitted through the bite of a species of sandfly of the genus Phlebotomus, releasing amastigote parasites that invade various organs of the body and eventually result in such conditions as anemia, splenomegaly and hepatomegaly. Although no vaccine exists for the disease, diagnostic techniques based not only on pathological tests, but more sophisticated detectors such as polymerase chain reaction, enzyme-linked immunosorbent assay, latex agglutination and immunochromatographic strip testing have been developed. Traditional treatment for the disease consists of two pentavalent antimonial drugs, sodium stibogluconate and meglumine antimoniate, but the growing resistance to these drugs has compelled scientists to search for new efficient compounds. (c) 2002 Prous Science. All rights reserved.