[Show abstract][Hide abstract] ABSTRACT: The title compound [1-(3,5-Dimethyl-2,3-dihydro-isoxazole-4-sulfonyl)-piperidin-4-yl)-diphenyl-methanol was synthesized and the product obtained was characterized by spectroscopic techniques and finally the structure was confirmed by X-ray diffraction studies. The compound crystallizes in the monoclinic crystal system with the space group P21/c and with unit cell parameters a = 8.5280(6) Å, b = 25.223(4) Å, c = 10.7060(17) Å, β = 99.879(8)°, and Z = 4. The structure reveals that the piperidine ring is in chair conformation. The geometry around the S atom is distorted tetrahedral. The structure exhibits both inter- and intramolecular hydrogen bonds of the type O—H···N and C—H···O.
[Show abstract][Hide abstract] ABSTRACT: Condensed-bicyclic triazolo-thiadiazoles were synthesized via an efficient "green" catalyst strategy and identified as effective inhibitors of PTP1B in vitro. The lead compound, 6-(2-benzylphenyl)-3-phenyl-[1,2,4]triazolo[1,3,4]thiadiazole (BPTT) was most effective against human hepatoma cells, inhibits cell invasion, and decreases neovasculature in HUVEC and also tumor volume in EAT mouse models. This report describes an experimentally unidentified class of condensed-bicyclic triazolo-thiadiazoles targeting PTP1B and its analogs could be the therapeutic drug-seeds.
[Show abstract][Hide abstract] ABSTRACT: The products of arachidonic acid metabolism by lipoxygenase (LOX) and cyclooxygenase (COX) significantly contribute to inflammation and carcinogenesis. Particularly, overproduction of leukotrienes and prostaglandins contribute to tumor growth by inducing formation of new blood vessels that sustain tumor cell viability and growth. Hence, search for novel anticancer drug via inhibition of LOX and COX enzymes constitutes an impressive strategy till date. In this context, a series of isoxazole derivatives were synthesized and screened for their anti-inflammatory activity via LOX and COX inhibition. Among these, 3-(3-methylthiophen-2-yl)-5-(3,4,5-trimethoxyphenyl)isoxazole (2b) showed significant inhibitory activity toward LOX and COX-2. Additionally, 2b showed a good inhibition of tumor growth, peritoneal angiogenesis, and ascite formation in Ehrlich ascites carcinoma (EAC) cell mouse model. Further, the in silico molecular studies also revealed that the compound 2b binds to the catalytic domain of LOX and COX-1 and COX-2 strongly with high atomic contact energy (ACE) score compared to standard drug. These initial pharmacological data support the fact that the compound 2b serves as the basis in developing anti-inflammatory and anticancer agents.
[Show abstract][Hide abstract] ABSTRACT: Malaria parasites currently gain resistance rapidly, across countries and continents. Hence, the discovery and development of novel chemical compounds, as well as scaffolds, with superior antimalarial activity remains an important priority, not only for the developing world. Our report describes the development, characterization and evaluation of novel bepotastine-based sulphonamide antimalarials inhibiting asexual stage development of Plasmodium (P.) falciparum parasites in vitro. Screening results showed potent inhibitory activity of a number of novel sulphonamides against P. falciparum at low micromolar concentrations, in particular in late-stage parasite development, as well as selectivity over mammalian cells. Based on computational studies we hypothesize N-myristoyltransferase as the target of the compounds developed here. Our results demonstrate the value of novel bepotastine-based sulphonamide compounds for targeting the asexual developmental stages of P. falciparum.
[Show abstract][Hide abstract] ABSTRACT: A series of 2,4,5-trisubstituted imidazoles and 1,2-disubstituted benzimidazoles catalyzed by
ZrO2-supported-β-cyclodextrin (ZrO2-β-CD) under solvent free conditions have been
synthesized and characterized by spectral methods. The nanoparticles (ZrO2-β-CD), prepared by
a simple one-pot-coprecipitation method and were characterized by PXRD, SEM, and TEM
techniques. The nano (ZrO2-β-CD) particles were found to be an effective heterogeneous
reusable catalyst for the effective synthesis of imidazoles and benzimidazoles under solvent free
conditions and all of the synthesized derivatives were evaluated for their antibacterial activity
against six bacterial strains.
[Show abstract][Hide abstract] ABSTRACT: 1,2,3-triazole-based heterocycles have previously been shown to possess significant
anticancer activity in various tumor models. In the present study, we attached a 1,2,3-triazole
moiety to the third position of a 1,2-benzisoxazole heterocycle via Copper (I)-catalyzed
azide-alkyne cycloaddition (CuAAC) with various alkynes and established for the title
compounds significant antiproliferative effect against human acute myeloid leukemia (AML)
cells. Among the tested compounds, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-
yl)benzo[d]isoxazole (PTB) was found to be the most potent antiproliferative agent with an
IC50 of 2 µM against MV4-11 cells using MTT assay. Notably, PTB induced cytotoxicity in
MOLM13, MOLM14 and MV4-11 cells with selectivity over normal bone marrow cells
(C57BL/6). Furthermore, PTB was found to induce cytotoxicity by increasing apoptosis of
AML cells (MOLM13, MOLM14 and MV4-11) as well as sub-G1 cell population and
apoptotic cells at submicromolar concentrations, as shown by flow cytometry and Annexin-V
staining, respectively. On the protein level we suggested histone deacetylases (HDACs) as
the potential protein target of those compounds in silico, and the predicted target was next
experimentally validated by measuring the variations in the levels of p21, cyclin D and
acetylation of histone H3 and tubulin. Molecular docking analysis of the title compounds
with the second deacetylase domain of HDAC6 displayed high degree of shape
complementarity to the binding site of the enzyme, forming multiple molecular interactions
in the hydrophobic region as well as a hydrogen bond to the phenol side-chain of Tyr-782.
Thus, 1,2,3-triazole derivatives appear to represent a class of novel, biologically active
ligands against histone deacetylases which deserve to be further evaluated in their
applications in the cancer field.
[Show abstract][Hide abstract] ABSTRACT: Drugs such as necopidem, saripidem, alpidem, zolpidem, and olprinone contain nitrogen-containing bicyclic, condensed-imidazo[1,2-α]pyridines as bioactive scaffolds. In this work, we report a high-yield one pot synthesis of 1-(2-methyl-8-aryl-substitued-imidazo[1,2-α] pyridin-3-yl)ethan-1-onefor the first-time. Subsequently, we performed in silico mode-of-action analysis and predicted that the synthesized imidazopyridines targets Phospholipase A 2 (PLA 2). In vitro analysis confirmed the predicted target PLA 2 for the novel imidazopyri-dine derivative1-(2-Methyl-8-naphthalen-1-yl-imidazo [1,2-α]pyridine-3-yl)-ethanone (compound 3f) showing significant inhibitory activity towards snake venom PLA 2 with an IC 50 value of 14.3 μM. Evidently, the molecular docking analysis suggested that imidazopyridine compound was able to bind to the active site of the PLA 2 with strong affinity, whose affinity values are comparable to nimesulide. Furthermore, we estimated the potential for oral bio-availability by Lipinski's Rule of Five. Hence, it is concluded that the compound 3f could be a lead molecule against snake venom PLA 2 .
PLoS ONE 07/2015; 10(7):e0131896. DOI:10.1371/journal.pone.0131896 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: First one pot protocol for the diastereoselective synthesis of Oxazolo[2,3-c]isoquinoline was achieved by metal-free, benzoic acid catalyzed reaction of 1,2,3,4-tetrahydroisoquinoline or trypoline with aldehydes under mild conditions via C–H, C–O bond functionalization. A new approach for the synthesis of highly substituted 1H-pyrrolo[2,1-c][1,4]oxazine was carried out.
[Show abstract][Hide abstract] ABSTRACT: Elevated activity of methionyl-tRNA synthetase (MRS) in many cancers renders it a possible drug target in this disease area, as well as in a series of parasitic diseases. In the present work, we report the synthesis and in vitro screening of a library of 1,3-oxazines, benzoxazines and quinoline scaffolds against human MRS. Among the compounds tested, 2-(2-butyl-4-chloro-1-(4-phenoxybenzyl)-1H-imidazol-5-yl)-5-(4-methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane (compound 21) and 2-(2-butyl-4-chloro-1-(4-nitrobenzyl)-1H-imidazol-5-yl)-2,4-dihydro-1H-benzo[d][1,3]oxazine (Compound 8) were found to be potent inhibitors of MRS. Additionally, those compounds significantly suppressed the proliferation of A549 and HCT116 cells with an IC50 value of 28.4, 17.7 and 41.9, 19.8 µM respectively. Molecular docking studies suggested that the ligand binding orientation overlaps with the original positions of both methionine and adenosine of MRS. This suggests the binding of compound 21 against MRS, which might leads the inhibitory activity towards cancer cells.
[Show abstract][Hide abstract] ABSTRACT: Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 μM) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading to ΔΨm dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.
PLoS ONE 06/2015; 10(6):e0127558. DOI:10.1371/journal.pone.0127558 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Medicinal plants are employed in the treatment of human ailments from time immemorial. Several studies have validated the use of medicinal plant products in arthritis treatment. Arthritis is a joint disorder affecting subchondral bone and cartilage. Degradation of cartilage is principally mediated by enzymes like matrix metalloproteinases (MMPs), hyaluronidases (HAase), aggrecanases and exoglycosidases. These enzymes act upon collagen, hyaluronan and aggrecan of cartilage respectively, which would in turn activate bone deteriorating enzymes like cathepsins and tartrate resistant acid phosphatases (TRAP). Besides, the incessant action of reactive oxygen species and the inflammatory mediators is reported to cause further damage by immunological activation. The present study demonstrated the anti-arthritic efficacy of tamarind seed extract (TSE). TSE exhibited cartilage and bone protecting nature by inhibiting the elevated activities of MMPs, HAase, exoglycosidases, cathepsins and TRAP. It also mitigated the augmented levels of inflammatory mediators like interleukin (IL)-1β, tumor necrosis factor-α, IL-6, IL-23 and cyclooxygenase-2. Further, TSE administration alleviated increased levels of ROS and hydroperoxides and sustained the endogenous antioxidant homeostasis by balancing altered levels of endogenous antioxidant markers. Overall, TSE was observed as a potent agent abrogating arthritis-mediated cartilage/bone degradation, inflammation and associated stress in vivo demanding further attention.
[Show abstract][Hide abstract] ABSTRACT: In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the
simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-
yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-
methoxyphenyl)piperazin-1-yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to
be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7 lM) over
COX1 (40.4 lM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific
inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of
COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study
reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-
specific inhibitors for anti-inflammatory therapy.