Exo-selective intermolecular Diels-Alder reaction by PyrI4 and AbnU on non-natural substrates.

The 100-year-old Diels-Alder reaction (DAr) is an atom economic and elegant organic chemistry transformation combining a 1,3-diene and a dienophile in a [4+2] cycloaddition leading to a set of products with several stereo centres and multiple stereoisomers. Stereoselective [4+2] cycloaddition is a challenge. Here, we describe two natural enzymes, PyrI4 and AbnU performing stereospecific intermolecular DAr on non-natural substrates. AbnU catalyses a single exo-stereoisomer by 32-fold higher than the background. PyrI4 catalyses the same stereoisomer (15-fold higher) as a major component (>50%). Structural, biochemical and fluorescence studies indicate that the dienophile enters first into the ß-barrel of the enzymes followed by the 1,3-diene, yielding a stereospecific product. However, if some critical interactions are disrupted to increase the catalytic efficiency, stereoselectivity is compromised. Since it is established that natural enzymes can carry out intermolecular DAr on non-natural substrates, several hundreds of Diels-Alderases available in nature could be explored.

Copper-Catalyzed Domino Addition, Hydroamination, and Cyclization: A Multicomponent Approach to Spiro Oxazolidinone Derivatives.

A copper-catalyzed one-pot multicomponent protocol has been developed for construction of spiro heterocycles. The domino approach leads to the synthesis of spiro oxazolidinones starting from ketones, arylacetylenes, and isocyanates via catalytic addition, hydroamination, and cyclization involving consecutive C-C, C-O, and C-N bond formations.

Highly functionalized tetrahydropyridines are cytotoxic and selective inhibitors of human puromycin sensitive aminopeptidase.

Efficient one-pot five-component synthetic protocols for highly functionalized tetrahydropyridines (THPs) and their biological evaluation have been illustrated. Synthesis of novel functionalized tetrahydropyridines containing differential substitutions at 2,6-positions has been achieved via a modified MCR. Cytotoxic studies of 23 synthesized compounds have been carried out against three different cell lines, namely A-549, HeLa and HepG2, wherein some compounds have displayed appreciable cytotoxicity. Further, investigation of enzyme inhibition by the synthesized THPs has been carried out against four members of M1 family aminopeptidases. Several compounds have selectively inhibited only one member of this enzyme family i.e., human puromycin sensitive aminopeptidase (hPSA). Among the compounds; 4b, 9b, 9e and 10a demonstrated best inhibition against hPSA.

Synthesis and antiproliferative activity of imidazo[1,2-a]pyrimidine Mannich bases.

A series of imidazo[1,2-a]pyrimidine Mannich bases were designed, synthesized in two phases. Mannich bases were obtained by one pot three component condensation of imidazo[1,2-a]pyrimidine with secondary amine or piperazine and excess of formaldehyde solution in methanol. The synthesized Mannich bases were screened for in vitro growth inhibition against a panel of 3 different human cancer cell lines. Most of the synthesized compounds exhibited antiproliferative activity with GI50 values ranging from 0.01 to 79.4 µM. Compounds 5e, 6b and 7k were found to be effective inhibitors of growth of all cell lines, with GI50 values similar to that of standard drug. The structure and activity relationship has been disclosed.

Discovery of Tröger's base analogues as selective inhibitors against human breast cancer cell line: design, synthesis and cytotoxic evaluation.

A library of structurally diverse Tröger's base analogues has been constructed via unusual amination of methylene bridge employing Vilsmeier-Haack conditions as well as by the incorporation of five and six membered heterocycles on the aromatic core of Tröger's base framework. The constructed structurally diverse frameworks were evaluated for their cytotoxic activities against a panel of three human cancer lines A549 (lung adenocarcinoma), MDAMB-231 (breast) and SK-N-SH (neuroblastoma). From the activity profile obtained, a redesign of Tröger's base analogues led to the construction of more potent molecular entities. The study led to development of a series of compounds with MDAMB-231 cell line specific cytotoxicity. Of the 30 compounds synthesized and evaluated, 7 compounds were found to possess cytotoxicity that is equivalent or better than standard drug doxorubicin against MDAMB-231 cell line while only one compound was found to be active against SK-N-SH cell line.

"One-pot" access to dihydrofurans via tandem oxidative difunctionalization and ring contraction of aminopyrans.

An operationally simple and efficient protocol for the construction of dihydrofuran derivatives has been accomplished via a sequential addition of N-chlorosuccinimide and a base to 2-amino-4H-pyran derivatives in alcohol medium. The one-pot protocol proceeding via tandem oxidative difunctionalization and ring contraction provides an entirely new strategy for the construction of the dihydrofuran skeleton.

Design, diversity-oriented synthesis and structure activity relationship studies of quinolinyl heterocycles as antimycobacterial agents.

The current study reports design and diversity oriented synthesis of novel bis heterocycles with a common 2-methyl, C-4 unsubstituted quinoline moiety as the central key heterocycle. Employing reagent based skeletal diversity approach; a facile synthesis of bis heterocycles with different heterocyclic rings at C-3 position of the quinoline moiety has been accomplished. A broad range of heterocyclic frameworks thus obtained were evaluated for their antimycobacterial activity. The active scaffolds were further explored by a parallel library generation in order to establish SAR. Further, low cytotoxicity against A549 cell line enhances the potential of the synthesized molecules as promising antimycobacterial agents.

Synthesis and biological screening of 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles as antiproliferative and anti-inflammatory agents.

A series of 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles were efficiently synthesized by oxidative cyclisation of N'-benzylidene-(1H-indol-3-yl)alkane hydrazides using di(acetoxy)iodobenzene. N'-Benzylidene-(1H-indol-3-yl)alkane hydrazides themselves were derived from simple indole-3-carboxylic acids. The 5-(alkyl(1H-indol-3-yl))-2-(substituted)-1,3,4-oxadiazoles were evaluated for their anti-inflammatory and anti-proliferative activities. Based on the results obtained structure and activity relationship (SAR) was established and a correlation between the activities was observed. Compound 6i and 6t showed best activity against proliferation of human cancer cell lines and as well as inflammation of rat paw edema.

Oxidative difunctionalization of 2-amino-4H-pyrans in iodobenzene diacetate and N-chlorosuccinimide: reactivity, mechanistic insights, and DFT calculations.

Oxidative difunctionalization of 2-amino-4H-pyrans was accomplished with iodobenzene diacetate (IBD) and N-chlorosuccinimide (NCS) reagents in alcoholic medium. 2-Amino-4H-pyrans undergo geminal dialkoxylation with the migration of an amino group (1a,b, 2a-i, 3a,b, and 4) in IBD, whereas with NCS addition of both chlorine and alkoxy groups takes place across the chromene double bond (6a-i).

Eco-friendly synthesis and biological evaluation of substituted pyrano[2,3-c]pyrazoles.

An ecofriendly green approach for synthesis of substituted pyrano[2,3-c]pyrazoles has been developed via a multicomponent one pot approach in aqueous ethanol medium under totally non-catalytic conditions. The synthesized compounds were evaluated for their antibacterial, anti-inflammatory and cytotoxic activities.

Structure activity relationship studies of imidazo[1,2-a]pyrazine derivatives against cancer cell lines.

Designed novel imidazo[1,2-a]pyrazine based inhibitors, synthesized by condensing α-aminopyrazines with α-halocarbonyl compounds followed by electrophilic substitutions. Cytotoxic effects on four cancer cell lines evaluated. Based on preliminary data, imidazo[1,2-a]pyrazine template redesigned to improve activity.