One pot synthesis, in silico study and evaluation of some novel flavonoids as potent topoisomerase II inhibitors.

A library of novel flavonoid derivatives with diverse heterocyclic groups was designed and efficiently synthesized. Structures of the newly synthesized compounds 4a-i and 8a-l have been characterized by 1H NMR, 13C NMR, MS and elemental analysis. Anticancer activities were evaluated against MCF-7, A549, HepG2 and MCF-10A by MTT based assay. Compared with the positive control Adriamycin, compounds 4a, 4b, 4c, 4d, 8d, 8e and 8j were found to be most active anti-proliferative compounds against human cancer cell line. We found that compounds 4a and 4c exhibited inhibition of enzyme topoisomerase II with IC50 values 10.28 and 12.38 µM, respectively. In silico docking study of synthesized compounds showed that compounds 4a and 4c have good binding affinity toward topoisomerase IIα enzyme and have placed in between DNA base pair at active site of enzyme. In silico ADME prediction results that flavonoid coumarin analogues 4a-i could be exploited as an oral drug candidate.

Insights of tankyrases: A novel target for drug discovery.

Tankyrases are the group of enzymes belonging to a class of Poly (ADP-ribose) polymerase (PARP) recently named ADP-ribosyltransferase (ARTD). The two isoforms of tankyrase i.e. tankyrase1 (TNKS1) and tankyrase2 (TNKS2) were abundantly expressed in various biological functions in telomere regulation, Wnt/ß-catenin signaling pathway, viral replication, endogenous hormone regulation, glucose transport, cherubism disease, erectile dysfunction, and apoptosis. The structural analysis, mechanistic information, in vitro and in vivo studies led identification and development of several classes of tankyrase inhibitors under clinical phases. In the nutshell, this review will drive future research on tankyrase as it enlighten the structural and functional features of TNKS 1 and TNKS 2, different classes of inhibitors with their structure-activity relationship studies, molecular modeling studies, as well as past, current and future perspective of the different class of tankyrase inhibitors.

Novel Benzylidenehydrazide-1,2,3-Triazole Conjugates as Antitubercular Agents: Synthesis and Molecular Docking.

BACKGROUND & OBJECTIVE: Novel 1,2,3-triazole based benzylidenehydrazide derivatives were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (MTB) H37Ra, M. bovis BCG and cytotoxic activity. Most of the derivatives exhibited promising in vitro potency against MTB characterized by lower MIC values. METHODS: Among all the synthesized derivatives, compound 6a and 6j were the most active against active and dormant MTB H37Ra, respectively. Compound 6d was significantly active against dormant and active M. bovis BCG. RESULTS: The structure activity relationship has been explored on the basis of anti-tubercular activity data. The active compounds were also tested against THP-1, A549 and Panc-1 cell lines and showed no significant cytotoxicity. Further, the synthesized compounds were found to have potential antioxidant with IC50 range = 11.19-56.64 µg/mL. The molecular docking study of synthesized compounds was performed against DprE1 enzyme of MTB to understand the binding interactions. CONCLUSION: Furthermore, synthesized compounds were also analysed for ADME properties and the potency of compounds indicated that, this series can be considered as a starting point for the developement of novel and more potent anti-tubercular agents in future.

New 2-Oxoindolin Phosphonates as Novel Agents to Treat Cancer: A Green Synthesis and Molecular Modeling.

The work reports the facile synthesis of novel α-aminophosphonate derivatives coupled with indole-2,3-dione moieties, namely the diethyl(substituted phenyl/heteroaryl)(2-(2-oxoindolin-3-ylidene)hydrazinyl)methylphosphonates derivatives 4(a⁻n). One-pot three component Kabachnik-Fields reactions were used to synthesize these derivatives. The reaction was carried out at room temperature by stirring in presence of ceric ammonium nitrate (CAN) as a green catalyst. The structures of the synthesized compounds were established by spectral studies. The synthesized derivatives 4(a⁻n) were evaluated for their in vitro anticancer activity against six human cancer cell lines by the SRB assay method. The cancer cell lines used in this research work are SK-MEL-2 (melanoma), MCF-7 (breast cancer), IMR-32 (neuroblastoma) MG-63 (human osteosarcoma), HT-29 (human colon cancer) and Hep-G2 (human hepatoma). All the synthesized derivatives inhibited the cell proliferation. Importantly, all the target compounds showed no cytotoxicity towards normal tissue cells (GI50 > 250 µM). A docking study was performed to predict the mode of action. Docking results indicate that the compounds have good binding with the enzyme tyrosine kinase as well as with microtubules, which makes them dual inhibitors. The result of in-silico bioavailability studies suggests that the compounds from the present series have good oral drug-like properties and are non-toxic in nature. In vivo acute oral toxicity study results indicate that the compounds can be considered safe, and therefore could be developed in the future as good anticancer agents or as leads for the design and synthesis of novel anticancer agents.

Ultrasound Assisted Synthesis of 4-(Benzyloxy)-N-(3-chloro-2-(substitutedphenyl)-4-oxoazetidin-1-yl) Benzamide as Challenging Anti-Tubercular Scaffold.

A series of ten novel derivatives of 4-(benzyloxy)-N-(3-chloro-2-(substituted phenyl)-4-oxoazetidin-1-yl) benzamide 6a⁻j were synthesized in good yield from the key compound 4-(benzyloxy)-N'-(substituted benzylidene) benzo hydrazide, called Schiff 's bases 5a⁻j, by Staudinger reaction ([2 + 2] ketene-imine cycloaddition reaction) with chloro acetyl chloride in the presence of catalyst tri ethylamine and solvent dimethyl formamide (DMF), by using ultra-sonication as one of the green chemistry tools. All the synthesised compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) and most of them showed promising activity with an IC50 value of less than 1 µg/mL. To establish the safety, all the synthesized compounds were further tested for cytotoxicity against the human cancer cell line HeLa and all 6a⁻j compounds were found to be non-cytotoxic in nature. The molecular docking study was carried out with essential enzyme InhA (FabI/ENR) of Mycobacterium responsible for cell wall synthesis which suggests that 6a and 6e are the most active derivatives of the series. The theoretical evaluation of cell permeability based on Lipinski's rule of five has helped to rationalize the biological results and hence the synthesized azetidinone derivatives 6a⁻j were also analyzed for physicochemical evaluation that is, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the results showed that all the derivatives could comply with essential features required for a potential lead in the anti-tubercular drug discovery process.

Ultrasound Promoted Green Synthesis, Docking Study of Indole Spliced Thiadiazole, α-amino Phosphonates as Anticancer Agents and Antityrosinase Agents.

BACKGROUND: Regardless of recent advances in the development of clinically authorized anticancer agents the number of deaths due to cancer is increasing day by day all over the world. The aim of this research work is to synthesis novel anticancer agents. METHOD: In this work, a new series of diethyl ((1H-indole-3-yl)((5-phenyl-1,3,4-thiadiazole-2-yl)amino) methyl)phosphonate derivatives 6(a-j) were designed and synthesized in Ultrasound by green protocol using Kabachnik-Fields reaction. The structures of the synthesized compounds were confirmed by spectral analysis such as elemental analyses, IR, 1H NMR, 13C NMR, 31P NMR and mass spectra. The synthesized compounds 6(a-j) were appraised for their in vitro anticancer activity against human cancer cell lines such as SK-MEL-2 (melanoma), IMR-32 (Neuroblastoma), HT-29(Colon) and also on normal murine embryonic fibroblast NIH/3T3 by Sulforhodamine B (SRB) assay, using Adriamycin as a standard drug. RESULT: The treatment of SK-MEL-2 cancer cells with 6i showed apoptosis and morphological changes like cell shrinkage, cell wall deformation and reduced number of viable cells. The synthesized derivatives were also evaluated for their anti-tyrosinase effect. Nearly all the tested derivatives have been found to be potent tyrosinase inhibitors. CONCLUSION: Nearly all the compounds were tested, the docking study was performed and indicates that the compounds have good binding interactions with tyrosine kinase enzyme. Absorption, Distribution, Metabolism and Elimination (ADME) properties of the synthesized compounds were also analyzed which manifested their potentiality to thrive as good oral drug candidates.

Structural insights of dipeptidyl peptidase-IV inhibitors through molecular dynamics-guided receptor-dependent 4D-QSAR studies.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are promising antidiabetic agents. Currently, several DPP-IV inhibitors have been approved for therapeutic use in diabetes mellitus. Receptor-dependent 4D-QSAR is comparatively a new approach which uses molecular dynamics simulations to generate conformational ensemble profiles of compounds representing a dynamic state of compounds at a target's binding site. This work describes a receptor-dependent 4D-QSAR study on triazolopiperazine derivatives. QSARINS multiple linear regression method was adopted to generate 4D-QSAR models. A model with 9 variables was found to have better predictive accuracy with [Formula: see text], [Formula: see text] (leave-one-out) = 0.592 and [Formula: see text] predicted = 0.597. The location of these 9 variables at the binding site of DPP-IV revealed the importance of the residues Val711, Tyr662, Tyr666, Val202, Asp200 and Thr199 in making critical interactions with DPP-IV inhibitors. The study of these critical interactions revealed the structural features required in DPP-IV inhibitors. Thus, in this study the importance of a halogen substituent on a phenyl ring, the extent of substitution on the triazolopiperazine ring, the presence of an ionizable amino group and the presence of a hydrophobic substituent that can bind deeper in binding pocket of DPP-IV were revealed.

Extended release delivery of erlotinib glutathione nanosponge for targeting lung cancer.

Systemic and uncontrolled administration of erlotinib hydrochloride (ETB) is associated with severe toxicity. A novel targeted and extended release nanosponge (NS) was synthesized from glutathione (GHS) by a one-step reaction between ß-cyclodextrin and pyromellitic dianhydride at room temperature for delivery of ETB in lung cancer. Characterization studies were performed using sophisticated instruments. In-vitro release study was performed in the presence of incremental concentrations of GHS which was analyzed using HPLC. Cell cytotoxicity study was evaluated on human lung cancer (A549) cell lines. In-vivo tumour inhibition and biodistribution of ETB-loaded GHS-NS (ETB-NS) were performed on BALB/c mice. NS obtained was spherical, size 212 ± 2.45 nm and high drug entrapment (92.34 ± 5.31%) (p < .001). In-vitro extended drug release (76.89 ± 0.1% release at 168 h), which was directly proportional to the concentration of GHS, demonstrated tumour targeting. There was enhanced in-vitro cytotoxicity and 97.5% inhibition in tumour growth on administering NS when compared to plain ETB (48% inhibition) indicating targeting of NS to the tumour site. Biodistribution study and in-vivo tumour growth inhibition study revealed drug release to the cancerous cell, thus preventing unnecessary drug exposure. ETB-NS exhibits extended drug release proportional to the external GSH concentration.

Ionic Liquid-Catalyzed Green Protocol for Multi-Component Synthesis of Dihydropyrano[2,3-c]pyrazoles as Potential Anticancer Scaffolds.

A series of 6-amino-4-substituted-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles 5a-j were synthesized via one-pot, four-component condensation reactions of aryl aldehydes 1a-j, propanedinitrile (2), hydrazine hydrate (3) and ethyl acetoacetate (4) under solvent-free conditions. We report herein the use of the Brønsted acid ionic liquid (BAIL) triethylammonium hydrogen sulphate [Et3NH][HSO4] as catalyst for this multi-component synthesis. Compared with the available reaction methodology, this new method has consistent advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. Selected synthesized derivatives were evaluated for in vitro anticancer activity against four human cancer cell lines viz. melanoma cancer cell line (SK-MEL-2), breast cancer cell line(MDA-MB-231), leukemia cancer cell line (K-562) and cervical cancer cell line (HeLa). Compounds 5b, 5d, 5g, 5h and 5j exhibited promising anticancer activity against all selected human cancer cell lines, except HeLa. Molecular docking studies also confirmed 5b and 5d as good lead molecules. An in silico ADMET study of the synthesized anticancer agents indicated good oral drug-like behavior and non-toxic nature.

Peptide deformylase: a new target in antibacterial, antimalarial and anticancer drug discovery.

Peptide deformylase (PDF) is a class of metalloenzyme responsible for catalyzing the removal of the N-formyl group from N-terminal methionine following translation. PDF inhibitors are moving into new phase of drug development. Initially, PDF was considered as an important target in antibacterial drug discovery; however genome database searches have revealed PDF-like sequences in parasites (P. falciparum) and human, widening the utility of this target in antimalarial and anticancer drug discovery along with antibacterial. Using structural and mechanistic information together with high throughput screening, several types of chemical classes of PDF inhibitors with improved efficacy and specificity have been identified. Various drugs like, GSK-1322322 (Phase II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. Developments in the field have prompted us to review the current aspects of PDFs, especially their structures, different classes of PDF inhibitors, and molecular modeling studies. In nut shell, this review enlightens PDF as a versatile target along with its inhibitors and future perspectives of different PDF inhibitors.

Microwave assisted synthesis and docking study of N-(2-oxo-2-(4-oxo-2-substituted thiazolidin-3ylamino)ethyl)benzamide derivatives as anticonvulsant agents.

Herewith, we report the design and synthesis of a series of N-(2-oxo-2((4-oxo-2-substituted thiazolidin-3yl)amino)ethyl) benzamide derivatives 7(a-j) under microwave irradiation, based on four component pharmacophoric model to get structural prerequisite indispensable for anticonvulsant activity. The synthesized derivatives were investigated in maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (sc-PTZ) induced seizure and neurotoxicity screening. All the test compounds were administered at a dose of 30, 100 and 300 mg/kg body weight at the time interval of 0.5 h and 4 h. The compounds were also evaluated for behavioral activity and toxicity study. The compound 7 h was found to be most active in MES model. The anticonvulsant screening data shows that 65% of the compounds were found active against MES model when compared to 35% sc-PTZ model. The computational parameter such as docking study, logP determination and ADME prediction were performed to exploit the results.

Synthesis and biological activity of substituted-4,5,6,7-tetrahydrothieno pyridines: a review.

4,5,6,7-Tetrahydrothieno pyridine is an important class of heterocyclic nucleus. Various 4,5,6,7-tetrahydrothieno pyridine derivatives have been synthesized and evaluated for various biological activities in different models with desired findings. Some analogs have shown potent biological activities and may be considered as lead molecule for the development of future drugs. Number of drug molecules are available in the market and many molecules are in clinical development containing 4,5,6,7-tetrahydrothieno pyridine nucleus as an important core. This review is an attempt to organize the chemical and biological aspects of 4,5,6,7-tetrahydrothieno pyridine analogs reported in last 20 year to till date. Review mainly focuses on the important role of the core in synthesis of drug or drug intermediates giving emphasis on synthetic schemes and biological activities of the different 4,5,6,7-tetrahydrothieno pyridine analogs.

Histone deacetylases as targets for multiple diseases.

Inhibition of Histone deacetylases (HDACs) has been emerged as important approach to reverse aberrant epigenetic changes associated with various cancerous and non-cancerous diseases. The field of histone deacetylase inhibitors (HDIs) is moving into a new phase of development. The structure of histone deacetylases is well-established and the active sites have been well identified. Various drugs targeting this enzyme are in the pipeline for the treatment of different diseases. Since first-generation HDAC inhibitors proved their clinical fruitfulness and also second generation inhibitors are rationally designed with improved specificity, experts believe that this class will emerge in the treatment of various diseases. Considering these facts present review focuses on HDACs and developments of HDIs in the treatment of various diseases.