[Show abstract][Hide abstract]ABSTRACT: Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.
[Show abstract][Hide abstract]ABSTRACT: In this study, we report the one-pot synthesis of substituted carbazole derivatives using nano cuprous oxide as a catalyst via intramolecular C-N bond forming reactions. Among the synthesized carbazoles, 3'-((3-acetyl-6-chloro-9H-carbazol-9-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (ACB) was identified as lead antiproliferative agent against lung cancer cell lines A549 and LLC with an IC50 of 13.6 and 16.4 µM respectively. Further, we found that lead compound suppresses the constitutive phosphorylation of STAT3 (Tyr-705) in A549, HCC-2279 and H1975 cells. We analyzed the levels of phospho-STAT3 and LSD1 in the nuclear extract of ACB treated HCC-2279 cells to evaluate the transcriptional activity of STAT3. We found the downregulation of phospho-STAT3 without any change in the expression of LSD1 indicating that ACB downregulates the transcriptional activity of STAT3. Molecular docking analysis revealed that ACB makes favorable interaction with Arg-609 and Ser-613 in pTyr site of SH2 domain of STAT3.
[Show abstract][Hide abstract]ABSTRACT: Hyperuricemia is a risk factor for not only gout, but also to a variety of disorders that affect the vital organ systems of the human body. The xanthine oxidase (XO) is the key enzyme in the production of uric acid and its inhibition can inhibit hyperuricemia. Although, XO inhibitor allopurinol is widely prescribed antigout agent but its use is not without any side effects. Previously, we described the synthesis of four novel thiadiazolopyrimidin-5-one analogues as effective XO inhibitors and molecular docking studies also confirmed this. When these analogues were tested in potassium oxonate treated rats, their serum uric acid and creatinine levels were dropped significantly from 4.85±0.03mg/dl to 1.21±0.01mg/dl and 0.92±0.02mg/dl to 0.40±0.02mg/dl respectively. Among the pyrimidine analogues tested, 6a was most potent. Histological examinations of both liver and kidney tissues exhibited severe necrosis in oxonate treated rats and pyrimidine analogues could significantly attenuate this with a correlative inhibitory profile of hepatic XO from the same rats. Our results demonstrate antihyperuricemic effect of novel thiadiazolopyrimidin-5-one analogues in oxonate treated rats, which can be further explored not only as antigout therapeutics but also in other systems where hyperuricemia is the driving cause of the disease.
No preview · Article · Feb 2016 · European journal of pharmacology
[Show abstract][Hide abstract]ABSTRACT: The title compound, C
O, crystallizes as a hemihydrate with the water molecule located on a twofold rotation axis. The piperidine ring has a chair conformation, whereas the triazole and the benzisoxazole rings are planar (r.m.s. deviations = 0.006 and 0.009 Å, respectively). The N—C and C—C bonds connecting the triazole and benzisoxazole rings, respectively, to the piperidine ring lie in equatorial positions. In the crystal, molecules related by a twofold rotation axis are linked
O—H...N hydrogen bonds involving the water molecule and a pair of C—H...N hydrogen bonds forming dimers. The dimers are linked
a pair of C—H...F hydrogen bonds leading to the formation of chains propagating along .
[Show abstract][Hide abstract]ABSTRACT: Transition-metal-free step-economical solid phase synthesis of 1,2-disubstituted 4-quinolones has been developed via novel regiospecific synthesis of enaminones. Notably, wide range of enaminones were synthesized by silica-supported solid-phase reaction in good to excellent yields. The transformation of enaminones to 1,2-disubstituted 4-quinolones and N-methyl-2-aryl-4-quinolone alkaloid was achieved in high yield by alumina-supported solid phase reaction. In addition, all the synthesised compounds were isolated directly in pure form from the reaction mixture by easy workup procedure.
[Show abstract][Hide abstract]ABSTRACT: Poly (ADP-ribose) polymerase (PARP) is a critical nuclear enzyme which safeguards genome stability from genotoxic insults and helps in DNA repair. Inhibition of PARP results into sustained DNA damage in cancer cell. PARP inhibitors are known to play an important role in chemotherapy as single agent in many DNA repair pathway deficient tumor cells or in combination with several other chemotherapeutic agents. In the present study, we synthesize and characterize novel pyridazine derivatives, and evaluate their potential to use as PARP inhibitors. Results show that pyridazine derivatives inhibited the PARP1 enzymatic activity at nanomolar range and showed anti-proliferative activity in leukemic cells. Interestingly, human leukemic cell line, Nalm6, in which PARP1 and PARP2 expression as well as intrinsic PARP activity are high, showed significant sensitivity for the novel inhibitors compared to other leukemic cells. Among the inhibitors, P10 showed maximum inhibition of intrinsic PARP activity and inhibited cell proliferation in Nalm6 cells. Besides P10 also showed maximum inhibition against purified PARP1 protein, which was comparable to Olaparib in our assays. Newly synthesized compounds also showed remarkable DNA trapping ability, which is a signature feature of many PARP inhibitors. Importantly, P10 also induced late S and G2/M arrest in Nalm6 cells, indicating accumulation of DNA damage. Therefore, we identify P10 as a potential PARP inhibitor, which can be developed as a chemotherapeutic agent.
[Show abstract][Hide abstract]ABSTRACT: The efficacy of thiazolidin-4-ones as synthons for diverse biological small molecules has given impetus to anti-bacterial studies. Our work aims to synthesize novel bioactive thiazolidin-4-ones using nano-MoO3 for the first time. The compelling advantage of using nano-MoO3 is that the recovered nano-MoO3 can be reused thrice without considerable loss of its catalytic activity. The synthesized thiazolidin-4-ones were tested for anti-bacterial activity against two strains of pathogenic bacteria, namely, Salmonella typhi and Klebsiella pneumoniae. Our results indicated that 3-(benzo[d]isoxazol-3-yl)-2-(3-methoxyphenyl)thiazolidine-4-one (compound 3b) showed significant inhibitory activity towards Salmonella typhi, in comparison with gentamicin. Furthermore, in silico target prediction presented the target of compound 3b as the FtsK motor domain of DNA translocase of Salmonella typhi. Hence, our hypothesis is that compound 3b may disrupt chromosomal segregation and thereby inhibit the division of Salmonella typhi. In addition, similarity searching showed that 34 compounds with a chemical similarity of 70% or higher to compound 3b, which were retrieved from ChEMBL, bound to targets associated with biological processes related to cell development in 36% of the cases. In summary, our work details novel usage of nano-MoO3 for the synthesis of novel thiazolidin-4-ones possessing anti-bacterial activity, and presents a mode-of-action hypothesis.
No preview · Article · Dec 2015 · New Journal of Chemistry
[Show abstract][Hide abstract]ABSTRACT: Bcl homologs prominently contribute to apoptotic resistance in cancer cells and serve as molecular targets in treatment of various cancers. Herein, we report the synthesis of biphenyl-adamantane derivatives by a ligand free palladium on carbon based Suzuki reaction using diisopropylamine as a base for the coupling of adamantane based aryl chloride with a variety of aryl boronic acids. Among the biphenyl derivatives synthesized, compound 3'-(adamantan-1-yl)-4'-methoxy-[1,1'-biphenyl]-3-ol (AMB) displayed cytotoxic activity against hepatocellular carcinoma cell lines without significantly affecting the normal cell lines. Further, AMB caused increased accumulation of the HCC cells in subG1 phase, decreased the expression of Bcl-2, Bcl-xL, cyclin D1, caspase-3, survivin and increased the cleavage of PARP in a time-dependent manner. In silico molecular interaction studies between Bcl homologs and AMB showed that the biphenyl scaffold is predicted to form π-π interactions with Phe-101 and Tyr-105 and the adamantyl fragment is predicted to occupy another hydrophobic region in the kink region of the binding groove. In summary, we report on the synthesis and biological characterization of adamantyl-tethered biphenylic compounds that induce apoptosis in tumor cells most likely by targeting Bcl homologs.
No preview · Article · Dec 2015 · Bioorganic & Medicinal Chemistry Letters
[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.
[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
Full-text · Article · Oct 2015 · Scientific Reports
[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.