Krishnaswamy Gunasekaran

Structure based design of compounds from natural sources for diabetes and inflammation

Medicinal plants and marine sources are important elements of indigenous medical systems worldwide. The natural drugs from medicinal plants and marine sources have received considerable interest in treatment of diabetes and inflammation. Based on literature, alpha glucosidase, aldose reductase and PTP1B enzymes were chosen as anti-diabetes targets and PLA2 was chosen for the anti-inflammatory target. In our study, plant and bromophenols (BPs) inhibitors were screened using High Throughput Virtual screening (HTVS) followed by Induced Fit Docking (IFD) studies were carried out against diabetes and inflammation targets. The IFD result of natural inhibitors has showed favorable docking score, glide energy and hydrogen bonds interactions with the active site residues. Some of the natural inhibitors successively satisfied all the in silico parameters among the others and seem to be potent inhibitors against diabetes and inflammation.

A novel guaiane sesquiterpene derivative, guai-2-en-10α-ol, from Ulva fasciata Delile inhibits EGFR/PI3K/Akt signaling and induces cytotoxicity in triple-negative breast cancer cells

A novel guaiane sesquiterpene derivative, guai-2-en-10α-ol, from Ulva fasciata Delile exhibits antimicrobial property. U. fasciata extract was reported to exhibit cytotoxicity against cancer. In the present study, we have studied the anticancer potential of the compound, guai-2-en-10α-ol, from U. fasciata. The compound showed selective cytotoxicity toward triple-negative breast cancer (TNBC) cell line (MDA MB-231) in a dose-dependent manner. In treated cells, the apoptotic hallmarks such as formation of apoptotic bodies, cell shrinkage, and nuclear condensation were observed. Many small molecules affect the function of cellular signaling pathways. As EGFR/PI3K/Akt pathway proteins are frequently altered in TNBC, we have studied the gene expression of key proteins of this pathway. The semiquantitative PCR results demonstrated the down-regulated expression of PDPK1 (positive regulator) and Akt (key activator) as well as up-regulated expression of PTEN (negative regulator), which suggested the interaction of guai-2-en-10α-ol with upstream protein. Further investigation showed the down-regulation of both PI3K and EGFR. As EGFR is the most upstream protein of the pathway, its protein level expression was investigated. Western blotting analysis confirmed the down-regulation of p-EGFR expression and activation of apoptosis upon compound treatment. Cell cycle analysis also evidenced the G1 phase arrest, which can be due to the inhibition of cell survival pathway. Computational studies showed the interaction of guai-2-en-10α-ol with Asp855 residue of EGFR kinase domain in active conformation. All these results demonstrate the anticancer potential of guai-2-en-10α-ol through EGFR/PI3K/Akt pathway.

2-(4-Bromo-benzo-yl)-1-ferrocenyl-spiro-[11H-pyrrolidizine-3,11'-indeno-[1,2-b]quinoxaline].

In the title compound, [Fe(C5H5)(C33H25BrN3O)], the fused four-ring system, 11H-indeno[1,2-b]quinoxaline is essentially planar, with a maximum deviation of 0.087 (3) Å from the least-squares plane of the attached benzene ring. The pyrrolidine rings adopt envelope conformation and make a dihedral angle of 51.76 (19)° with each other. The cyclopentadiene rings of the ferrocenyl moiety have an eclipsed conformation. The Br atom deviates by 0.0190 (9) Å from the attached benzene ring. The molecular structure features an intramolecular C—H⋯N interaction, which generates an S(8) ring motif. The crystal packing features C—H⋯O interactions, which generate R 2 2(18) centrosymmetric dimers, as well as C—H⋯π interactions.

6-Ferrocenoyl-7-phenyl­spiro­[hexa­hydro­pyrrolo­[1,2-c][1,3]thia­zole-5,11′-indeno­[1,2-b]quinoxaline]

In the title compound, [Fe(C5H5)(C32H24N3OS)], both the thiazolidine ring and the pyrrolidine ring adopt an envelope conformation, with the S atom and the phenyl-bearing C atom, respectively, as the flaps. The thiazolidine ring mean plane makes a dihedral angle of 59.08 (11)° with the pyrrolidine ring mean plane, which in turn makes a dihedral angle of 83.40 (10)° with the cyclopentane ring, indicating that the latter two rings are almost orthogonal to one another. In the crystal, a pair of C—H⋯O hydrogen bonds link the molecules forming inversion dimers. The dimers are linked via π–π interactions [centroid–centroid distance = 3.7764 (10) Å] involving the quinoxaline moieties forming chains propagating along [1-10].

Crystal structure of methyl 1-methyl-3,5-diphenyl-7-tosyl-3,6,7,11b-tetra-hydro-pyrazolo-[4',3':5,6]pyrano[3,4-c]quinoline-5a(5H)-carboxyl-ate.

In the title compound, C35H31N3O5S, the piperidine ring adopts an envelope conformation, with the methine C atom as the flap, and the pyran ring adopts a sofa conformation. The mean planes of these two rings are almost normal to one another, making a dihedral angle of 85.96 (5)°. The two phenyl rings, one attached to the pyrazole ring and the other to the pyran ring, are inclined to one another by 65.41 (11)°. They are inclined to the mean planes of the rings to which they are attached by 12.59 (11) and 70.09 (9)°, respectively. There is an intramolecular C—H⋯π interaction involving the tosylate methyl group and the phenyl ring attached to the pyrazole ring. In the crystal, molecules are linked by C—H⋯π interactions, forming ribbons parallel to (10-2). The ribbons are linked by slipped parallel π–π interactions involving inversion-related pyrazole rings [inter-centroid distance = 3.672 (2) Å], forming slabs parallel to (001). A preliminary report of this structure has been published [Bakthadoss et al. (2014 ▶). Eur. J. Org. Chem. pp. 1505–1513].

2-Amino-5-fluoro­benzoic acid

In the title compound, C7H6FNO2, the molecule is almost planar (r.m.s. deviation for the non-H atoms = 0.015 Å) and an intramolecular N—H⋯O hydrogen bond closes an S(6) ring. In the crystal, inversion dimers linked by pairs of O—H⋯O hydrogen bonds generate R 2 2(8) loops. Weak N—H⋯F hydrogen bonds, short F⋯F contacts [2.763 (2) Å] and aromatic π–π stacking interactions [centroid–centroid separation = 3.5570 (11) Å] are also observed in the crystal structure.

1,7,8,9,10,10-Hexachloro-4-(thio­phen-2-ylmeth­yl)-4-aza­tricyclo­[5.2.1.02,6]dec-8-ene-3,5-dione

In the title compound, C14H7Cl6NO2S, the six-membered ring of the azatricyclo system has a boat conformation whereas the five-membered rings have an envelope conformation. The thiophene ring and the ring of the succinimide moiety enclose a dihedral angle of 67.2 (1)°. The crystal packing is stabilized by weak intermolecular C—H⋯O hydrogen bonds.

tert-Butyl 3-(8-bromo-4H,10H-1,2-oxazolo[4,3-c][1]benzoxepin-10-yl)-2-methyl-1H-indole-1-carboxyl­ate

In the title compound, C25H23BrN2O4, the seven-membered ring adopts a twisted-boat conformation. The indole ring system is planar within 0.021 (2) Å and the ester group [–C(=O)—O—C–] is almost coplanar with it [dihedral angle = 3.0 (2)°]. The conformation of the ester group is influenced by intramolecular C—H⋯O interactions. In the crystal structure, molecules are linked into chains along the b axis by C—H⋯N hydrogen bonds.