Assembly of Benzothiazine and Triazole in a Single Molecular Entity: Synthesis of -Oxicam Derived Novel Molecules as Potential Antibacterial/ Anti-cancer Agents.

BACKGROUND: Benzothiazine derivatives, because of their various biological activities have attracted particular attention in Med Chem and drug discovery efforts. The synthetic modifications of 1,2-benzothiazine 1,1-dioxides have been undertaken in order to explore and identify novel compounds or new analogues possessing promising biological activities. In our effort we have designed -oxicam derived bezothiazine-1,2,3-triazole derivatives as potential antibacterial agents. METHODS: These compounds were synthesized via a multi-step sequence involving the Cu catalyzed azide- alkyne cycloaddition (CuAAC) as a key step. The CuAAC proceeded at room temperature in DMF to afford 26 novel molecules in good (70-90%) yields. RESULTS: All these compounds were tested for their antibacterial properties against four strains of bacterial microorganisms and subsequently cytotoxic properties against lung and colon cancer cell lines. The compound 4e showed activities against majority of the bacterial species used (nearly comparable to amoxicillin, ciprofloxacin and ofloxacin against P. vulgaris) whereas 4d and 4f showed cytotoxicities selective towards cancer cells. CONCLUSION: The present bezothiazine-1,2,3-triazole framework represents a new template for the identification of novel and potent antibacterial/anticancer agents.

Design, Synthesis and Antibacterial Evaluation of Compounds Based on New Benzoxepine-oxime-1,2,3-triazole Hybrid.

BACKGROUND: A library of compounds related to the new benzoxepine-oxime-1,2,3-triazole hybrid was created as probable antibacterial agents. Their synthesis involved a Cu-catalyzed azidealkyne cycloaddition (CuAAC) as a key step to construct the desired 1,2,3-triazole ring. Thus the click reaction between the appropriate alkyne containing the benzoxepine-oxime framework with aryl azides afforded the target compounds in good yields. METHOD: To assess their antibacterial properties all the synthesized compounds were tested using four bacterial strains consisting of one Gram-positive and three Gram-negative species. RESULTS & CONCLUSION: These compounds were generally found to be effective towards gram -ve species and one of them showed selective cytotoxicity against lung cancer cell line.

1,2,3-Triazole-nimesulide hybrid: Their design, synthesis and evaluation as potential anticancer agents.

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC50 ∼6-10µM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60-70% at 10µM) that was supported by the docking studies (PLP score 87-94) in silico.

1H-1,2,3-Triazolyl-substituted 1,3,4-oxadiazole derivatives containing structural features of ibuprofen/naproxen: Their synthesis and antibacterial evaluation.

1H-1,2,3-Triazolyl-substituted 1,3,4-oxadiazole derivatives containing structural features of ibuprofen/naproxen were synthesized for the first time using a Cu catalyzed azide-alkyne cycloaddition (CuAAC) strategy. An optimized reaction condition was established for this purpose and twenty new compounds were synthesized using this methodology. Several of these compounds showed good to reasonable antibacterial activities when tested against three gram-positive and three gram-negative species. The compound 4m i.e. N-(2-chlorophenyl)-2-(4-((5-(1-(6-methoxynaphthalen-2-yl)ethyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)acetamide showed promising activities across both the species.

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.

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.

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 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.

Yb(OTf)3 catalyzed new cascade reaction: a facile assembly of fused quinazolinones.

A one-pot Yb(III)-mediated cascade reaction has been developed leading to small molecules based on a novel structural motif, i.e. quinazolin-4-one moiety fused with an isoquinoline ring, for potential inhibition of TNF-α.

Synthesis and structure analysis of cyclodehydration product of piroxicam: a metabolite detected in dogs and monkeys.

We report here a novel synthesis of 6-methyl-6H-7-oxopyrido[1,2-a]pyrimido[5,4-c]-1,2-benzothiazine-5,5-dioxide or cyclodehydration product of piroxicam, a metabolite detected in dogs and monkeys that was synthesized in 6% yield earlier. The reaction of benzoyl chloride with piroxicam in the presence of triethylamine afforded the piroxicam metabolite in good yield. A comparison of spectral data of the synthesized compound with the reported values remained inconclusive. The structure of the compound was confirmed unambiguously by single-crystal X-ray analysis.

Transition-metal/Lewis acid free synthesis of acyl benzothiophenes via C-C bond forming reaction.

A simple and single-step synthesis of 2- and 3-acyl substituted benzothiophenes has been described via environmentally benign acylation of benzothiophene with in situ generated acyl trifluoroacetates. Both aliphatic and aromatic carboxylic acids participated in trifluoroacetic anhydride/phosphoric acid mediated C-C bond forming reactions under solvent-free conditions affording acyl benzothiophenes in good overall yields.