[Show abstract][Hide abstract] ABSTRACT: In this work, we describe the 'green' synthesis of novel 6-(adamantan-1-yl)-2-substituted-imidazo[2,1-b][1,3,4]thiadiazoles (AITs) by ring formation reactions using 1-(adamantan-1-yl)-2-bromoethanone and 5-alkyl/aryl-2-amino1,3,4-thiadiazoles on a nano material base in ionic liquid media. Given the established activity of imidazothiadiazoles against M. tuberculosis , we next examined the anti-TB activity of AITs against the H 37 Rv strain using Alamar blue assay. Among the tested compounds 6-(adamantan-1-yl)-2-(4-methoxyphenyl)imi-dazo[2,1-b][1,3,4]thiadiazole (3f) showed potent inhibitory activity towards M. tuberculosis with an MIC value of 8.5 μM. The inhibitory effect of this molecule against M. tuberculosis was comparable to the standard drugs such as Pyrazinamide, Streptomycin, and Ciproflox-acin drugs. Mechanistically, an in silico analysis predicted sterol 14α-demethylase (CYP51) as the likely target and experimental activity of 3f in this system corroborated the in silico target prediction. In summary, we herein report the synthesis and biological evaluation of novel AITs against M. tuberculosis that likely target CYP51 to induce their antimycobacter-ial activity.
PLoS ONE 11/2015; 10(10):e0139798. DOI:10.1371/journal.pone.0139798 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: DNA minor groove binders are an important class of chemotherapeutic agents. These small molecule inhibitors interfere with various cellular processes like DNA replication and transcription. Several benzimidazole derivatives showed affinity towards the DNA minor groove. In this study we show the synthesis and biological studies of a novel benzimidazole derivative (MH1), that inhibits topoisomerase II activity and in vitro transcription. UV-visible and fluorescence spectroscopic methods in conjunction with Hoechst displacement assay demonstrate that MH1 binds to DNA at the minor groove. Cytotoxic studies showed that leukemic cells are more sensitive to MH1 compared to cancer cells of epithelial origin. Further, we find that MH1 treatment leads to cell cycle arrest at G2/M, at early time points in Molt4 cells. Finally multiple cellular assays demonstrate that MH1 treatment leads to reduction in MMP, induction of apoptosis by activating CASPASE 9 and CASPASE 3. Thus our study shows MH1, a novel DNA minor groove binder, induces cytotoxicity efficiently in leukemic cells by activating the intrinsic pathway of apoptosis.
[Show abstract][Hide abstract] ABSTRACT: Phospholipase A2 (PLA2) is known to regulate inflammation and hence it is considered as a validated drug-target by medicinal chemists. In this report, we have identified and considered a highly ranked ligand from the ZINC-drug-like compounds database that targets PLA2 via the MOLPRINT-2D based chemoinformatics drug-design approach. The computationally predicted lead molecule was found to contain a core moiety of a chromene ring, which is well known for its varied biological properties. Here, a novel and efficient retro-synthetic protocol for the synthesis of highly substituted chromene libraries was made. A one-pot synthesis of chromene was carried out using different aromatic primary alcohols, malononitrile and 4-hydroxy coumarin in the presence of a mild oxidant mixture called T3P®-DMSO, followed by a Suzuki coupling reaction to obtain the lead molecules. All of the tested compounds of the chromene series displayed inhibition of the venom PLA2 in the range of 12 to 68 μM. Among the tested compounds, 2-amino-4-(2′-methyl-[1,1′-biphenyl]-4-yl)-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile (7b) showed maximum inhibitory efficacy against venom PLA2 with an IC50 value of 12.5 μM. Furthermore, the designed PLA2 ligands bound to the active site of venom PLA2, whose binding affinity was comparable to nimesulide, indicating that the chromene moiety containing ligands could be novel lead-structures that serve as anti-inflammatory agents.
[Show abstract][Hide abstract] ABSTRACT: Thrombocytopenia is one of the most frequently observed secondary complications in many pathological conditions including liver diseases, where hyperbilirubinemia is very common. The present study sought to find the cause of thrombocytopenia in unconjugated hyperbilirubinemic conditions. Unconjugated bilirubin (UCB), an end-product of heme catabolism, is known to have pro-oxidative and cytotoxic effects at high serum concentration. We investigated the molecular mechanism underlying the pro-apoptotic effect of UCB on human platelets in vitro, and followed it up with studies in phenylhydrazine-induced hyperbilirubinemic rat model and hyperbilirubinemic human subjects. UCB is indeed found to significantly induce platelet apoptotic events including elevated endogenous reactive oxygen species generation, mitochondrial membrane depolarization, increased intracellular calcium levels, cardiolipin peroxidation and phosphatidylserine externalization (p < 0.001) as evident by FACS analysis. The immunoblots show the elevated levels of cytosolic cytochrome c and caspase activation in UCB-treated platelets. Further, UCB is found to induce mitochondrial ROS generation leading to p38 activation, followed by downstream activation of p53, ultimately resulting in altered expression of Bcl-2 and Bax proteins as evident from immunoblotting. All these parameters conclude that elevated unconjugated bilirubin causes thrombocytopenia by stimulating platelet apoptosis via mitochondrial ROS-induced p38 and p53 activation
[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.