Sarbani Pal

Isocoumarin and Its Derivatives: An Overview on their Synthesis and Applications

The prevalence of isocoumarins in numerous natural products that exhibit a wide range of biological activities has generated a continued and enormous interest among synthetic and medicinal chemists. The isocoumarin framework represents one of the privileged structures for the development of natural product-inspired compounds of potential biological interest. Considerable efforts have been de- voted towards the synthesis of isocoumarins via either traditional or transition-metal catalyzed reactions. Among the metal catalyzed re- actions, the use of Cu, Pd, Ag, Ru, Rh or Ir salts/complexes for the construction of isocoumarin ring are noteworthy. Among the other methodologies, halo-lactonization emerged as a practical process. Apart from preparing a variety of isocoumarins and thienopyranones, synthesis of naturally occurring and bioactive isocoumarins have been carried out by using cutting edge technologies. This review article will briefly cover all these aspects along with the synthetic utility of isocoumarins, highlighting recent developments.

Chemical modifications of nimesulide

We describe here the chemical modifications of nimesulide either via direct N-acylation or via a two-step process involving reduction of the nitro group followed by regioselective acylation/sulfonylation of the resulting arylamine. The acylation step of the second approach was found to be faster than acylation of nimesulide. A number of N-acylated and N-sulfonylated derivatives of N-(4-amino-2-phenoxy phenyl)methanesulfonamide obtained from nimesulide were conveniently prepared in good to excellent yields. Some of the compounds synthesized were tested for cyclooxygenase inhibition and few of them showed selectivity for COX-2.

Novel 1-alkynyl substituted 1,2-dihydroquinoline derivatives from nimesulide (and their 2-oxo analogues): A new strategy to identify inhibitors of PDE4B

A number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these compounds were synthesized by using Sonogashira coupling as a key step. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized are presented.

High speed synthesis of pyrazolones using microwave-assisted neat reaction technology

Descrevemos uma sintese rapida e pratica de pirazolonas, na ausencia de solvente, sob irradiacao de microondas. Esta metodologia sintetica envolve a reacao de b-cetoesteres com hidrazinas substituidas e nao-substituidas e oferece uma preparacao simples e direta de diferentes pirazolonas com alta regioseletividade. Essas pirazolonas podem existir em diferentes formas tautomericas em solucao e o anel 2-aril-pirazol-3-ona permanece torcido em relacao ao plano da pirazolona no estado cristalino. O mecanismo da reacao e proposto levando em conta a regiosseletividade. Uma das pirazolonas obtidas nesse processo foi usada na preparacao de um derivado espirociclohexanona de significativo potencial biologico. A high speed, solvent-free, and practical synthesis of pyrazolones under microwave irradiation is described. This greener synthetic methodology involves the reaction of b-keto ester with substituted or unsubstituted hydrazine and provides a simple and straightforward one-pot approach for the synthesis of a variety of pyrazolone derivatives with high regioselectivity. These pyrazolones can exist in different tautomeric forms in solution and the aryl ring of 2-aryl pyrazol-3-ones remain twisted with respect to the pyrazole plane in the crystal state. Mechanism of the reaction accounting the regioselectivity has been proposed. One of the pyrazolones obtained via this process was utilized to prepare a spirocyclohexanone derivative of potential biological significance.

Derivatization of Enolic OH of Piroxicam: a Comparative Study on Esters and Sulfonates

Varios esteres e sulfonatos derivados da piroxicam foram preparados por acilacao e sulfonacao da hidroxila fenolica da piroxicam. Todos os compostos foram avaliados quanto a estabilidade quimica e as propriedades de inibicao da ciclooxigenase. Os dados sugeriram que os esteres poderiam ser o ponto de partida para o desenvolvimento de farmacos em potencial. Os sulfonatos derivados, preparados pela primeira vez, apresentaram estabilidade. Entre eles, um demonstrou uma moderada seletividade de inibicao da COX-2 sobre a COX-1 e teria menor efeito colateral para o sistema gastrintestinal que a piroxicam devido ao grupo OH enolico mascarado. Um mecanismo plausivel para o processo de acilacao e sulfonacao foi proposto, envolvendo a participacao da porcao da piridina presente na piroxicam. A estrutura molecular de um dos esteres foi estabelecida, pela primeira vez, por meio de analise cristalografica dos dados de raio-X de difracao de po.

Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells

A new class of 1,2,3-triazol derivatives derived from nimesulide was designed as potential inhibitors of PDE4B. Synthesis of these compounds was carried out via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required azide was prepared via the reaction of aryl amine (obtained from nimesulide) with α-chloroacetyl chloride followed by displacing the α-chloro group by an azide. Some of the synthesized compounds showed encouraging PDE4B inhibitory properties in vitro that is >50% inhibition at 30 μM that were supported by the docking studies of these compounds at the active site of PDE4B enzyme (dock scores ~ -28.6 for a representative compound). Two of these PDE4 inhibitors showed promising cytotoxic properties against HCT-15 human colon cancer cells in vitro with IC50 ~ 21-22 μg/mL.

Novel benzoxepine-1,2,3-triazole hybrids: synthesis and pharmacological evaluation as potential antibacterial and anticancer agents

A number of pre-designed benzoxepine-1,2,3-triazole hybrids were synthesized for the first time using a Cu-catalyzed azide–alkyne cycloaddition (CuAAC) strategy. Thus, a remarkably rapid click reaction of 7,9-disubstituted (Z)-4-(azidomethyl)-5-chloro-2,3-dihydrobenzo[b]oxepine with terminal alkynes at room temperature in DMF afforded twenty novel (Z)-1-((5-chloro-2,3-dihydrobenzo[b]oxepin-4-yl)methyl)-1H-1,2,3-triazole derivatives in good to excellent yields. All these compounds were tested for their antibacterial properties against four strains of bacterial microorganisms including two Gram-positive and two Gram-negative species. Some of them showed better activity against Gram-negative bacteria (Escherichia coli) over the Gram-positive strains, indicating the special effectiveness of the present class of compounds towards Gram-negative species. These compounds also showed cytotoxicity against lung and colon cancer cell lines.

Synthesis of 2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-triazole derivatives: Their evaluation as potential PDE 4B inhibitors possessing cytotoxic properties against cancer cells

The 2,2,4-trimethyl-1,2-dihydroquinolinyl substituted 1,2,3-triazole derivatives were designed as potential inhibitors of PDE4B. These compounds were synthesized via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required alkynes were prepared from nimesulide via N-propargylation and then nitro group reduction followed by a CAN mediated modified Skraup reaction of the resulting amine. All the synthesized compounds showed PDE4B inhibitory properties in vitro at 30μM with two compounds showing >50% inhibition that were supported by the in silico docking results of these compounds at the active site of PDE4B. Three of these PDE4 inhibitors showed promising cytotoxic properties against A549 human lung cancer cells in vitro with IC50 ∼8-9μM.

Design of new hybrid template by linking quinoline, triazole and dihydroquinoline pharmacophoric groups: A greener approach to novel polyazaheterocycles as cytotoxic agents

A new hybrid template designed by linking three pharmacophoric groups, for example, quinoline, triazole and dihydroquinoline moieties have been used for the generation of a library of molecules as potential cytotoxic agents. Synthesis of these polyazaheterocycles were carried out by using a strategy that involved one-pot sequential azidation and CuAAC in water under mild conditions. A number of 1,4-disubstituted 1,2,3-triazoles possessing quinolinylmethylene at N-1 and 1,2-dihydroquinolinyl methylene at C-4 as different substituents were synthesized and evaluated for their cytotoxic effects against various cancer cells. Some of them showed encouraging activities against lung cancer cells and one of them showed inhibition of PDE4 indicating the potential medicinal value of these novel polyazaheterocycles.

Nimesulide Based Novel Glycolamide Esters: Their Design, Synthesis, and Pharmacological Evaluation

The nimesulide based novel glycolamide esters were designed and synthesized for the first time via a three-step method starting from nimesulide. Structures of the synthesized compounds were confirmed by spectroscopic analysis. All the synthesized compounds were examined for their cytotoxic effects in vitro, some of which showed significant cytotoxic activities against HCT-15 human colon cancer cell line.