Synthesis of privileged scaffolds by using diversity-oriented synthesis.

An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14.

Synthesis, structure activity relationship and mode of action of 3-substitutedphenyl-1-(2,2,8,8-tetramethyl-3,4,9,10-tetrahydro-2H,8H-pyrano[2,3-f]chromen-6-yl)-propenones as novel anticancer agents in human leukaemia HL-60 cells.

A novel class of 3-substitutedphenyl-1-(2,2,8,8-tetramethyl-3,4,9,10-tetrahydro-2H,8H-pyrano[2,3-f]chromen-6-yl)-propenones were designed, synthesized and evaluated for their antiproliferative activity against the human cancer cell lines of diverse origin. Structure activity relationship was elucidated with various substitutions on the benzene ring and these variations significantly affected the potency. Most of the twelve tested compounds inhibited the growth of aggressive cancer cell lines. Moreover, three compounds 4j, 4k and 4l displayed excellent cytotoxic profile by inhibiting >90% cell proliferation in HL-60 and Caco-2 cells at 50 µM concentration. Further studies to elucidate the mode of action revealed that these three compounds induced G0/G1 cell cycle arrest and apoptosis, which was accompanied by loss of mitochondrial membrane potential, DNA fragmentation and nuclear morphology in HL-60 cells.

Diminutive effect on T and B-cell proliferation of non-cytotoxic α-santonin derived 1,2,3-triazoles: a report.

α-Santonin derived new series of 1,2,3-triazoles synthesized through Azide-Alkyne Huisgen 1,3-dipolar cycloaddition reaction between substituted aryl azide and a propargylated α-desmotrosantonin were bio-evaluated for their diminutive effect on ConA induced T-cell and LPS induced B-cell proliferation. Interestingly, most of the synthesized compounds showed better immunosuppressant activity than α-santonin. Triazole derivatives 9, 10, 17, 18, 29, and 30 displayed significant diminutive effect on cell proliferation. Compounds 12 and 13 were found selective against ConA T-cell proliferation exhibiting >90% inhibition at 1 × 10(-6) M concentration. The present study resulted in identification of several triazole derivatives as effective immunosuppressive agents.

Design, solvent free synthesis, and antimicrobial evaluation of 1,4 dihydropyridines.

Here in, we report the usage of cellulose sulfuric acid as a heterogeneous eco friendly catalyst for the synthesis of 1,4 dihydropyridines under solvent free conditions via Hantzsch three component reaction of an aldehyde, ethyl acetoacetate and ammonium acetate at 100 °C for 2-5 h. In silico studies were performed on twenty two possible 1,4 dihydropyridines (DHPs) analogues against K(+) channel receptor (KcsA). In order to validate in silico studies, thirteen compounds were synthesized and evaluated as antibacterials against twenty seven ESBL isolates of Klebsiella pneumoniae and Escherichia coli.

Reagent-based DOS: developing a diastereoselective methodology to access spirocyclic- and fused heterocyclic ring systems.

Herein, we report a diversity-oriented-synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N-heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N-heterocycles. The two-step sequence starts with a chiral-bicyclic-lactam-directed enolate-addition/substitution step. This step is followed by a ring-closure onto the built-in scaffold electrophile, thereby leading to stereoselective carbocycle- and spirocycle-formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug-like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell-lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry.

Development and Validation of a Rapid RP-UPLC Method for the Simultaneous Estimation of Bambuterol Hydrochloride and Montelukast Sodium from Tablets.

A rapid, simple, sensitive and selective analytical method was developed by using reverse phase ultra performance liquid chromatographic technique for the simultaneous estimation of bambuterol hydrochloride and montelukast sodium in combined tablet dosage form. The developed method is superior in technology to conventional high performance liquid chromatography with respect to speed, resolution, solvent consumption, time, and cost of analysis. Elution time for the separation was 6 min and ultra violet detection was carried out at 210 nm. Efficient separation was achieved on BEH C18 sub-2-µm Acquity UPLC column using 0.025% (v/v) trifluoro acetic acid in water and acetonitrile as organic solvent in a linear gradient program. Resolutions between bambuterol hydrochloride and montelukast sodium were found to be more than 31. The active pharmaceutical ingredient was extracted from tablet dosage from using a mixture of methanol, acetonitrile and water as diluent. The calibration graphs were linear for bambuterol hydrochloride and montelukast sodium in the range of 6.25-37.5 µg/ml. The percentage recoveries for bambuterol hydrochloride and montelukast sodium were found to be in the range of 99.1-100.0% and 98.0-101.6%, respectively. The test solution was found to be stable for 7 days when stored in the refrigerator between 2-8°. Developed UPLC method was validated as per International Conference on Harmonization specifications for method validation. This method can be successfully employed for simultaneous estimation of bambuterol hydrochloride and montelukast sodium in bulk drugs and formulations.

A new antifungal briarane diterpenoid from the gorgonian Junceella juncea Pallas.

A new 8-hydroxy briarane diterpenoid (compound 1) with antifungal activity was isolated along with known compounds (2-5) from the gorgonian coral Junceellajuncea. On the basis of spectroscopic data (1D and 2D NMR, MS), the structure of the compound 1 was established as (1S,2S,8S,9S,10S,11R,12R,14S,17R)-11,20-epoxy-14-(3-methylbutanoyl)-2,9,12-triacetoxy-8-hydroxybriar-5(16)-en-18,7-olide. Compound 1 exhibited significant activity against fungi (Aspergillus niger, Candida albicans and Penicillium notatum) but the other compounds (2-5) did not exhibit the activity against fungi.

Enantioselective synthesis of spirooxoindoles via chiral auxiliary (bicyclic lactam) controlled SNAr reactions.

A highly efficient enantioselective S(N)Ar reaction of chiral acyl bicyclic lactam with substituted-2,4-dinitrobenzenes was developed, affording products containing quarternary stereogenic centers. They are further utilized towards an enantioselective synthesis of spirooxoindoles.

Synthesis of fluorinated analogues of SJG-136 and their DNA-binding potential.

A series of C2-exo-fluorounsaturated pyrrolobenzodiazepines (PBDs) have been synthesized. These C2-exo-fluorounsaturated PBD dimers have exhibited remarkable DNA-binding affinity.