Discovery of a tetrazolyl β-carboline with and osteoprotective activity under estrogen-deficient conditions.

β-Carbolines have been assessed for osteoclastogenesis. However, their effect on osteoblasts during estrogen deficiency is still unclear. Here, a series of novel piperazine and tetrazole tag β-carbolines have been synthesized and examined for osteoblast differentiation .

An insight into tetrahydro-β-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial agents.

A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives () have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant activity against the promastigote (IC from 0.59 ± 0.

gem-Dithioacetylated indole derivatives as novel antileishmanial agents.

In this communication we report a serendipitously discovered hybrid molecule 1, combining fragment of 3 (an in vivo active antileishmanial molecule) with HS donor moiety (known for bimodal behavior of cytoprotection and apoptosis), as antileishmanial agent. Compound 1 suppresses 99.82% parasitemia of L.

Dual targeting of MDM2 with a novel small-molecule inhibitor overcomes TRAIL resistance in cancer.

Mouse double minute 2 (MDM2) protein functionally inactivates the tumor suppressor p53 in human cancer. Conventional MDM2 inhibitors provide limited clinical application as they interfere only with the MDM2-p53 interaction to release p53 from MDM2 sequestration but do not prevent activated p53 from transcriptionally inducing MDM2 expression. Here, we report a rationally synthesized chalcone-based pyrido[ b ]indole, CPI-7c, as a unique small-molecule inhibitor of MDM2, which not only inhibited MDM2-p53 interaction but also promoted MDM2 degradation.

Identification of a diverse indole-2-carboxamides as a potent antileishmanial chemotypes.

A novel series of highly diverse indole-2-carboxamides was synthesized utilizing the isocyanide based multicomponent reaction (IMCR)-post modification approach and were identified as potential antileishmanial chemotype. Among the synthesized 18 analogues, 12 analogues exhibited better antileishmanial activity against intracellular amastigotes form of Leishmania donovani (IC50 values of 0.6-7.

HPLC-MS-MS Method Development and Validation of Antileishmanial Agent, S010-0269, in Hamster Serum.

A rapid, sensitive and simple high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of the antileishmanial agent, S010-0269, in hamster serum. A Discovery HS C-18 column (5 μm, 50 × 4.6 mm) maintained at 40°C was utilized for chromatographic separation with mobile phase [acetonitrile: aqueous ammonium acetate (0.

New class of methyl tetrazole based hybrid of (Z)-5-benzylidene-2-(piperazin-1-yl)thiazol-4(%H)-one as potent antitubercular agents.

In search of potential therapeutics for tuberculosis, we describe here the synthesis and in vitro antitubercular activity of a novel series of thiazolone piperazine tetrazole derivatives. Among all the synthesized derivatives, four compounds (10, 14, 20 and 33) exhibited more potent activity (MIC=3.08, 3.

Base mediated 7-exo-dig intramolecular cyclization of Ugi-propargyl precursors: a highly efficient and regioselective synthetic approach toward diverse 1,4-benzoxazepine-5(2H)-ones.

A metal-free facile and efficient two-step synthetic protocol for the preparation of 1,4-benzoxazepine-5(2H)-one derivatives has been developed. The protocol involves Ugi reaction followed by K2CO3 mediated highly regioselective 7-exo-dig intramolecular cyclization of less-nucleophilic oxygen with the pendant alkyne moiety of an Ugi-propargyl precursor to afford the 1,4-benzoxazepine-5(2H)-one derivatives in good to excellent yields.

Discovery of triazine mimetics as potent antileishmanial agents.

The World Health Organization has classified the leishmaniasis as a major tropical disease. The discovery of new compounds for leishmaniasis is therefore a pressing concern for the anti-infective research program. We have synthesized 19 compounds of triazine dimers as novel antileishmanial agents.

Synthesis of novel β-carboline based chalcones with high cytotoxic activity against breast cancer cells.

A series of novel β-carboline based chalcones was synthesized and evaluated for their cytotoxic activity against a panel of human cancer cell lines. Among them we found that two of the compounds 7c and 7d, showed marked anti-proliferative activity in a panel of solid tumor cell lines with highest effect in breast cancer. The compounds 7c and 7d showed an IC50 of 2.

Investigation of Ugi-4CC derived 1H-tetrazol-5-yl-(aryl) methyl piperazinyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid: synthesis, biology and 3D-QSAR analysis.

Novel series of 7-piperazinylquinolones with tetrazole derivatives were synthesized and evaluated for their antibacterial activity against various strains of Staphylococcus aureus. All the synthesized compounds showed significant in vitro antibacterial activity against Gram-positive bacteria whereas some compounds displayed moderate activity against Gram-negative bacteria. Among all the synthesized compounds, compounds (6a-c, 6e-g, 6i-k, 6m, 6'f and 6'm) were found to be more effective with MIC ranging from (0.

Design and synthesis of a new class of 4-aminoquinolinyl- and 9-anilinoacridinyl Schiff base hydrazones as potent antimalarial agents.

A series of novel 4-aminoquinolinyl and 9-anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine-sensitive strain 3D7 and the chloroquine-resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17, 20, and 21 displayed good activity against the 3D7 strain with IC50 values ranging from 19.

Triazino indole-quinoline hybrid: a novel approach to antileishmanial agents.

A novel series of 1,2,4-triazino-[5,6b]indole-3-thione covalently linked to 7-chloro-4-aminoquinoline have been synthesized and evaluated for their in vitro activity against extracellular promastigote and intracellular amastigote form of Leishmania donovani. Among all tested compounds, compounds 7a and 7b were found to be the most active with IC50 values 1.11, 0.

Synthesis and bioevaluation of novel 4-aminoquinoline-tetrazole derivatives as potent antimalarial agents.

A series of novel tetrazole derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities against both chloroquine-senstive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum as well as for cytotoxicity against VERO cell lines. Most of the synthesized compounds exhibited potent antimalarial activity as compared to chloroquine against K1-strain. Compounds with significant in vitro antimalarial activity were then evaluated for their in vivo efficacy in Swiss mice against Plasmodium yoelii following both intraperitoneal (ip) and oral administration, wherein compounds 20 and 23 each showed in vivo suppression of 99.

Discovery of a new class of natural product-inspired quinazolinone hybrid as potent antileishmanial agents.

The high potential of quinazolinone containing natural products and their derivatives in medicinal chemistry led us to discover four novel series of 53 compounds of quinazolinone based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal activity against intracellular amastigotes (IC50 from 0.65 ± 0.

Molecular cloning and characterization of glucose-6-phosphate dehydrogenase from Brugia malayi.

Glucose-6-phosphate dehydrogenase (G6PD), a regulatory enzyme of the pentose phosphate pathway from Brugia malayi, was cloned, expressed and biochemically characterized. The Km values for glucose-6-phosphate and nicotinamide adenine dinucleotide phosphate (NADP) were 0.25 and 0.

Synthesis and biological evaluation of a new class of 4-aminoquinoline-rhodanine hybrid as potent anti-infective agents.

Synthesis of novel 4-aminoquinoline-rhodanine hybrid using inexpensive starting materials via easy to operate methodology, and their biological activity is reported. All the compounds were screened for their in vitro antimalarial activity against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) strains of Plasmodium falciparum, and their cytotoxicity toward VERO cell line. Compounds 9, 19, 21 and 23 exhibited excellent antimalarial activity with IC50 value ranging from 13.

Synthesis of perspicamide A and related diverse analogues: their bioevaluation as potent antileishmanial agents.

The first protocol for the synthesis of perspicamide A and related diverse analogues has been developed from economical and readily available starting materials. Furthermore, a few synthesized analogues, 24a, 24b, 24c, 24d, and 24l, exhibited potent activity against Leishmania donovani with IC(50) values ranging from 3.75 to 10.

A natural product inspired hybrid approach towards the synthesis of novel pentamidine based scaffolds as potential anti-parasitic agents.

A natural product inspired molecular hybridization approach led us to a series of novel pentamidine based pyrimidine and chalcone scaffolds. All the hybrids were evaluated for their anti-leishmanial potential. Most of the screened compounds have showed significant in vitro anti-leishmanial activity with less cytotoxicity in comparison to the standard drugs (pentamidine, sodium stibogluconate, and miltefosine).

Access to indole- and pyrrole-fused diketopiperazines via tandem Ugi-4CR/intramolecular cyclization and its regioselective ring-opening by intermolecular transamidation.

An efficient approach for the synthesis of indole- and pyrrole-fused diketopiperazines has been developed. This protocol involves the Ugi four-component reaction (U-4CR) followed by an intramolecular cyclization of the Ugi products at room temperature to afford the desired products in good to excellent yields. In addition, it is interesting to report the subsequent regioselective ring-opening of diketopiperazine unit occurring via an intermolecular transamidation reaction under mild condition, resulting in the formation of highly functionalized indole-2-carboxamides and pyrrole-2-carboxamides.

Dihydrofolate reductase as a therapeutic target for infectious diseases: opportunities and challenges.

Infectious diseases caused by parasites continue to take a massive toll on human health in the poor regions of the world. Filling the anti-infective drug-discovery pipeline has never been as challenging as it is now. The organisms responsible for these diseases have interesting biology with many potential biochemical targets.

A ligand-free Pd-catalyzed cascade reaction: an access to the highly diverse isoquinolin-1(2H)-one derivatives via isocyanide and Ugi-MCR synthesized amide precursors.

A novel ligand-free palladium-catalyzed cascade reaction for the synthesis of highly diverse isoquinolin-1(2H)-one derivatives from isocyanide and amide precursors synthesized by Ugi-MCR has been developed. A broad variety of acids, amines, and isocyanides were used as starting materials for Ugi-MCR leading to various amide precursors, which in turn provided entry into diverse isoquinolin-1(2H)-one derivatives. The reaction proceeds through tandem isocyanide insertion with intramolecular cyclization followed by a Mazurciewitcz-Ganesan type sequence to provide isoquinoline-1(2H)-one derivatives in moderate to good yields.

Skeletal diverse synthesis of N-fused polycyclic heterocycles via the sequence of Ugi-type MCR and CuI-catalyzed coupling/tandem Pictet-Spengler reaction.

Several diversity-oriented syntheses of N-fused polycyclic heterocycles have been demonstrated but most of them are based on point diversity within the same library and usually involve time-consuming sequential multistep syntheses, which also suffer from low yields and/or poor precursor scopes. We have developed a new strategy for the syntheses of skeletal diverse N-fused polycyclic compounds via an Ugi-type MCR followed by a CuI-catalyzed coupling reaction or tandem Pictet-Spengler reaction. This two-step sequence provides eight distinct skeleton of fused {6-5-5-6}, {5-5-5-6}, {6-5-6-6}, and {5-5-6-6} ring systems that have applications in medicinal chemistry and chemical genetics too.

Cyanuric chloride catalyzed mild protocol for synthesis of biologically active dihydro/spiro quinazolinones and quinazolinone-glycoconjugates.

We have developed an efficient cyanuric chloride (2,4,6-trichloro-1,3,5-triazine, TCT) catalyzed approach for the synthesis of 2,3-dihydroquinazolin-4(1H)-one (3a-3x), 2-spiroquinazolinone (5, 7), and glycoconjugates of 2,3-dihydroquinazolin-4(1H)-one (10a, 10b) derivatives. The reaction allows rapid cyclization (8-20 min) with 10 mol % cyanuric chloride to give skeletal complexity in good to excellent yield. We believe that this novel procedure may open the door for the easy generation of new and bioactive quinazolinones.

Bridging gaps in discovery and development: chemical and biological sciences for affordable health, wellness and sustainability.

To commemorate 2011 as the International Year of Chemistry, the Indian Society of Chemists and Biologists organized its 15th International Conference on 'Bridging Gaps in Discovery and Development: Chemical and Biological Sciences for Affordable Health, Wellness and Sustainability' at Hotel Grand Bhagwati, in association with Saurashtra University, Rajkot, India. Anamik Shah, President of the Indian Society of Chemists and Biologists, was organizing secretary of the conference. Nicole Moreau, President of the International Union of Pure and Applied Chemistry and Secretary General of the Comité National de la Chimie, National Centre for Scientific Research France, was chief guest of the function.