Design and Synthesis of 2-Phenylindolizine Acetamides: Molecular Docking, in Vitro Antimicrobial and Anticancer Activity Evaluation.

In the present work, we synthesized a small library of 2-phenylindolizine acetamide derivatives 7a-i and studied their biological activity. The synthesis was accomplished starting with easily available starting material phenacyl bromide 1 proceeding through the key intermediate 6-methyl-7-nitro-2-phenylindolizine 4. All the compounds 7a-i were characterized using spectroscopy viz., 1H-NMR, 13C NMR, FTIR, and mass spectrometry. Interestingly, 2-phenylindolizine scaffolds 7c, 7f and 7g revealed a remarkable antibacterial activity against relevant organisms S. aureus, E. coli, S. pneumoniae, P. aeruginosa. The target compounds 7e and 7h showed excellent anticancer activity against Colo-205 and MDA-MB-231 cell lines with IC50 values of 68.62, 62.91, 54.23 and 46.34 µM respectively. Additionally, all the 2-phenylindolizine acetamide derivatives 7a-i were subjected to molecular docking prediction by Autodock 4.2. Compounds 7a, 7f and 7c exhibited very good hydrogen bonding amino acid interactions Asp83 (2.23 Å), Asp83 (2.08 Å), His74 (2.05 Å), His76 (1.71 Å), Ser80 (1.05 Å) with active site of Topoisomerase-IV from S. pneumoniae (4KPE). Further, the compounds 7a-i have revealed acceptable ranges for drug-likeliness properties upon evaluation using SwissADME for ADMET and physiochemical properties.

New tetrazolopyrrolidine-1,2,3-triazole analogues as potent anticancer agents: design, synthesis and molecular docking studies.

1,2,3-Triazole and tetrazole derivatives bearing pyrrolidines are found to exhibit notable biological activity and have become useful scaffolds in medicinal chemistry for application in lead discovery and optimization. We report design, synthesis and molecular docking studies of tetrazolyl-1,2,3-triazole derivatives (7a-i) bearing pyrrolidine moiety and evaluating their anticancer activity against four cancer cell lines viz. Hela, MCF-7, HCT-116 and HepG2. The structures of the new compounds were ascertained by spectral means IR, NMR: 1H &13C and Mass spectrum. From the studies compounds7a and 7i exhibited significant anticancer activity against the Hela cell line with IC50 = 0.32 ± 1.00, 1.80 ± 0.22 µM when compared to reference drug Doxorubicin (IC50 = 2.34 ± 0.11 µM), whereas 7h, 7i, and 7b were found to be active against MCF-7, HCT-116 and HepG2 cell lines with IC50 = 3.20 ± 1.40, 1.38 ± 0.06 and 0.97 ± 0.12 µM respectively. Notably 7a exhibited highest conventional hydrogen bondings TyrA:40, SerA:17, LysA:117, AlaA:146, Tyr218 with 3HB4and SerA:17, LysA:117, AlaA:146, TyrA:40 with 6IBZ and docking energy - 10.85, - 8.21 kcal/mol respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME. The results of the in vitro and in silico studies suggest that the tetrazole incorporated pyrrolidine-triazoles may possess the ideal structural requirements for further developing new anticancer agents.

Chimerical pyrene-based [7]helicenes as twisted polycondensed aromatics.

Chimerical pyrene-based dibenzo[7]helicene rac-1 and 2H-pyran[7]helicene (M,R,R)-(-)-2, in which two pyrene subunits are fused to the [7]helicene/[7]heterohelicene scaffold, were synthesised by means of Ni(0) - or Co(I) -mediated [2+2+2] cycloisomerisation of dipyrenyl-acetylene-derived triynes. Pyrene-based dibenzo[7]helicene 1 was obtained in enantioenriched form by enantioselective cycloisomerisation under Ni(0) /QUINAP catalysis (57 % ee) or in enantiopure form by racemate resolution by liquid chromatography on a chiral column. 1,3-Allylic-type strain-controlled diastereoselective cycloisomerisation was employed in the synthesis of enantiopure (M,R,R)-(-)-2. Physicochemical properties of 1 and 2 encompassing the helicity assignment, stability to racemisation, X-ray crystal structure, UV/Vis, experimental/calculated electronic circular dichroism and fluorescence spectra were studied. Accordingly, comparison of the X-ray crystal structure of (M,R,R)-(-)-2 with calculated structures (DFT: B3LYP/cc-pVDZ, B97D/cc-pVDZ) indicated that its helical backbone is slightly over-flattened owing to intramolecular dispersion forces between tert-butylated pyrene subunits. Both 1 and 2 are fluorescent (with quantum yields in dichloromethane of ΦF =0.10 and 0.17, respectively) and are suggested to form intramolecular excimer states upon excitation, which are remarkably stabilised and exhibit large Stokes shifts (296 and 203 nm, respectively).

Intramolecular Povarov reactions involving 3-aminocoumarins.

A series of pentacyclic heterocyclic systems (15 examples, 69-89%) have been synthesized using intramolecular Povarov reactions involving 3-aminocoumarins and O-cinnamylsalicylaldehydes. The Povarov adducts are formed with high selectivity for the trans,trans relative stereochemistry in the newly-formed [6,6] fused ring system. One example of a Povarov adduct featuring a new [6,5] fused ring system is reported. In this case, cis,trans relative stereochemistry was preferred.

Povarov reactions involving 3-aminocoumarins: synthesis of 1,2,3,4-tetrahydropyrido[2,3-c]coumarins and pyrido[2,3-c]coumarins.

Condensation of 3-aminocoumarin (5) with 4-nitrobenzaldehyde (8) afforded a 2-azadiene (9), which reacted with various electron-rich alkenes (10 examples) in the presence of Yb(OTf)3 to afford 1,2,3,4-tetrahydropyrido[2,3-c]coumarins. Yields were generally good, but the diastereomeric ratios were highly variable. The products arose through a formal [4 + 2] cycloaddition (inverse electron demand Diels-Alder reaction) followed by tautomerization. As such, these are examples of the Povarov reaction. A range of 1,2,3,4-tetrahydropyrido[2,3-c]coumarins was then synthesized using a three-component version of this reaction, which involves in situ formation of the 2-azadiene component. Some of these products were converted into the corresponding pyrido[2,3-c]coumarins upon treatment with various oxidants, the most effective of which proved to be nitrous gases.