- Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy
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Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2′3′- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2′3′-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.
- Gangar, Mukesh,Goyal, Sandeep,Raykar, Digambar,Khurana, Princy,Martis, Ashwita M.,Goswami, Avijit,Ghoshal, Ishani,Patel, Ketul V.,Nagare, Yadav,Raikar, Santosh,Mukherjee, Apurba,Cyriac, Rajath,Paquin, Jean-Fran?ois,Kulkarni, Aditya
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supporting information
(2021/12/20)
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- Novel fluoroquinolones containing 2-arylamino-2-oxoethyl fragment: Design, synthesis, evaluation of antibacterial and antituberculosis activities and molecular modeling studies
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Novel substituted fluoroquinolone derivatives, compounds 6–20 were designed, synthesized, and evaluated for antituberculosis and antibacterial activity. Antibacterial activities of the compounds were determined and compound 14 was found to be the most pot
- Bozdeveci, Arif,Krishna, Vagolu Siva,Sriram, Dharmarajan,Alpay Karao?lu, ?engül,Kü?ükgüzel, ?lkay,Kulaba?, Necla,Türe, Asl?
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- Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations
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A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of L-dopa and L-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 μM and 0.17 μM in the presence of L-tyrosine and L-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 μM for L-tyrosine and 9.30 μM for L-dopa. According to Lineweaver–Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 μM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.
- Hosseinpoor, Hona,Moghadam Farid, Sara,Iraji, Aida,Askari, Sadegh,Edraki, Najmeh,Hosseini, Samanesadat,Jamshidzadeh, Akram,Larijani, Bagher,Attarroshan, Mahshid,Pirhadi, Somayeh,Mahdavi, Mohammad,Khoshneviszadeh, Mehdi
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- In silico approach using free software to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based schiff bases
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In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of
- Abdalla, Ashraf N.,Almalki, Faisal A.,El Hassab, Mahmoud A.,Gouda, Ahmed M.,Shawky, Ahmed M.
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- Novel 1,2,4-triazole analogues as mushroom tyrosinase inhibitors: synthesis, kinetic mechanism, cytotoxicity and computational studies
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We have created a novel series of mushroom tyrosinase inhibitors with 1,2,4-triazole as fundamental skeleton. The target compound 1,2,4-triazol-3-ylthio)-N-phenyl acetamide derivatives 9(a–l) were synthesized by the reaction of 4- and 5-substituted 1,2,4-triazole-3-thiol derivatives 6(a–c) with 2-chloro-N-sub/un-substituted phenyl acetamide derivatives 8(a–d) under basic condition. By using the analytical techniques for instance, FTIR, LC–MS, 1H NMR and 13C NMR, the structural verification was evaluated. The novel series of the target compounds 9(a–l) has been scanned for biological activity (mushroom tyrosinase inhibition potential) which demonstrates adequate results. Interestingly, compound 9k (IC50 = 0.0048 ± 0.0016?μM) exhibits 3500 times more activity compared with standard drug kojic acid (IC50 = 16.8320 ± 1.1600?μM) against mushroom tyrosinase inhibitor. Furthermore, the cytotoxicity experiment was carried out for the highly effective target compounds (9d, 9i, 9j and 9k) by using MTT assay method for A375 human melanoma cells to define the nontoxic performance of the most effective compounds ranging from 1 to 25?μM. Furthermore, the molecular docking study delivers the thought concerning the interface of the ligand with an enzyme. Also, the dynamic simulation was accomplished for compound 9k to govern the plausible binding model.
- Vanjare, Balasaheb D.,Mahajan, Prasad G.,Dige, Nilam C.,Raza, Hussain,Hassan, Mubashir,Han, Yohan,Kim, Song Ja,Seo, Sung-Yum,Lee, Ki Hwan
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p. 2089 - 2106
(2020/05/18)
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- A novel series of substituted 1,2,3-triazoles as cancer stem cell inhibitors: Synthesis and biological evaluation
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An alarming increase in global death toll resulting from cancer incidents, particularly due to multidrug resistance and reduced efficacy as a consequence of target mutations, has compelled us to look for novel anticancer agents. Cancer stem cells (CSCs),
- Padhariya, Komal N.,Athavale, Maithili,Srivastava, Sangeeta,Kharkar, Prashant S.
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- Novel (thio)barbituric-phenoxy-N-phenylacetamide derivatives as potent urease inhibitors: synthesis, in vitro urease inhibition, and in silico evaluations
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A novel series of (thio)barbituric-phenoxy-N-phenylacetamide derivatives 7a-l was synthesized and evaluated against Helicobacter pylori urease. The latter assay revealed that all the synthesized compounds 7a-l (IC50 = 0.69 ± 0.33–2.47 ± 0.23?μM
- Sedaghati, Saeb,Azizian, Homa,Montazer, Mohammad Nazari,Mohammadi-Khanaposhtani, Maryam,Asadi, Mehdi,Moradkhani, Fatemeh,Ardestani, Mehdi Shafiee,Asgari, Mohammad Sadegh,Yahya-Meymandi, Azadeh,Biglar, Mahmood,Larijani, Bagher,Sadat-Ebrahimi, Seyed Esmaeil,Foroumadi, Alireza,Amanlou, Massoud,Mahdavi, Mohammad
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- Design, synthesis, antibacterial and quorum quenching studies of 1,2,5-trisubstituted 1,2,4-triazoles
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Abstract: In view of discovering novel bioactive molecules, 1-phenyl-1H-2-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)-3-(N-aryl-carbamoylmethylthio)-1,2,4-triazoles (8a–n) were designed and synthesized in good yield. Preliminary antibacterial activity was tested against Chromobacterium violaceum and Xanthomonas campestris pv. Campestris (Xcc). Out of 14 derivatives, compound 8g selectively possessed antibacterial activity against C. violaceum. Further derivatives that possessed an electron-withdrawing group and halogen atoms in N-phenylacetamide moiety were moderately active against Xcc (plant pathogen). After observing the reduction of violacein production through plate assay, compounds 8a, 8c, 8h, 8i and 8m were subjected to quantification of quorum sensing inhibition. Compounds with the electron-withdrawing group in N-phenylacetamide moiety showed admirable activity with > 80% inhibition of violacein. Mainly compound 8c which was inactive against the growth of bacteria were identified as excellent QSI which could be a lead compound for further development. Graphic abstract: One of the best approaches to acquire anti-virulence strategies and new direction for the discovery of antibacterial drugs[Figure not available: see fulltext.]
- Sathyanarayana, Reshma,Bajire, Sukesh Kumar,Poojary, Boja,Shastry, Rajesh P.,Kumar, Vasantha,Chandrashekarappa, Revanasiddappa Bistuvalli
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p. 1051 - 1066
(2020/10/22)
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- Design, synthesis and in silico insights of new 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives with potent anticancer and multi-kinase inhibitory activities
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Aiming to obtain an efficient anti-proliferative activity, structure- and ligand-based drug design approaches were expanded and utilized to design and refine a small compound library. Subsequently, thirty-two 7,8-disubstituted-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives were selected for synthesis based on the characteristic pharmacophoric features required for PI3K and B-Raf oncogenes inhibition. All the synthesized compounds were evaluated for their in vitro anticancer activity. Compounds 17 and 22c displayed an acceptable potent activity according to the DTP-NCI and were further evaluated in the NCI five doses assay. To validate our design, compounds with the highest mean growth inhibition percent were screened against the target PI3Kα and B-RafV600E to confirm their multi-kinase activity. The tested compounds showed promising multi-kinase activity. Compounds 17 and 22c anticancer effectiveness and multi-kinase activity against PI3Kα and B-RafV600E were consolidated by the inhibition of B-RafWT, EGFR and VEGFR-2 with IC50 in the sub-micromolar range. Further investigations on the most potent compounds 17 and 22c were carried out by studying their safety on normal cell line, in silico profiling and predicted ADME characteristics.
- Abdel Gawad, Nagwa M.,El Kerdawy, Ahmed M.,George, Riham F.,Georgey, Hanan H.,Mohamed, Abdalla R.
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- C?H Methylation of Iminoamido Heterocycles with Sulfur Ylides**
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The direct methylation of N-heterocycles is an important transformation for the advancement of pharmaceuticals, agrochemicals, functional materials, and other chemical entities. Herein, the unprecedented C(sp2)-H methylation of iminoamido heterocycles as nucleoside base analogues is described. Notably, trimethylsulfoxonium salt was employed as a methylating agent under aqueous conditions. A wide substrate scope and excellent level of functional-group tolerance were attained. Moreover, this method can be readily applied to the site-selective methylation of azauracil nucleosides. The feasibility of gram-scale reactions and various transformations of the products highlight the synthetic potential of the developed method. Combined deuterium-labeling experiments aided the elucidation of a plausible reaction mechanism.
- Ghosh, Prithwish,Kwon, Na Yeon,Kim, Saegun,Han, Sangil,Lee, Suk Hun,An, Won,Mishra, Neeraj Kumar,Han, Soo Bong,Kim, In Su
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supporting information
p. 191 - 196
(2020/10/29)
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- Naproxen based 1,3,4-oxadiazole derivatives as EGFR inhibitors: Design, synthesis, anticancer, and computational studies
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A library of novel naproxen based 1,3,4-oxadiazole derivatives (8–16 and 19–26) has been synthesized and screened for cytotoxicity as EGFR inhibitors. Among the synthesized hy-brids, compound2-(4-((5-((S)-1-(2-methoxynaphthalen-6-yl)ethyl)-1,3,4-oxadiazol-2-ylthio)methyl)-1H-1,2,3-triazol-1-yl)phenol(15) was the most potent compound against MCF-7 and HepG2cancer cells with IC50 of 2.13 and 1.63 μg/mL, respectively, and was equipotent to doxorubicin (IC50 1.62 μg/mL) towards HepG2. Furthermore, compound 15 inhibited EGFR kinase with IC50 0.41 μM compared to standard drug Erlotinib (IC50 0.30 μM). The active compound induces a high percentage of necrosis towards MCF-7, HePG2 and HCT 116 cells. The docking studies, DFT and MEP also supported the biological data. These results demonstrated that these synthesized naproxen hybrids have EGFR inhibition effects and can be used as leads for cancer therapy.
- Alam, Mohammad Mahboob,Alfaifi, Mohammad Y.,Alfaifi, Sulaiman Y. M.,Almalki, Abdulraheem S. A.,Alsenani, Nawaf I.,Alsharif, Meshari A.,Elbehairi, Serag Eldin I.,Elhenawy, Ahmed A.,Malebari, Azizah M.,Nazreen, Syed
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- Synthesis and Anti-Inflammatory Properties of Substituted 5-(Tetrahydro-4-phenyl-2H-pyran-4-yl)-4H-1,2,4-triazole-3-thiols
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Abstract: 5-(Tetrahydro-4-phenyl-2H-pyran-4-yl)-4H-1,2,4-triazole-3-thiol was synthesized by the reaction of 4-phenyltetrahydropyran-4-carbonyl chloride with thiosemicarbazide and subsequent cyclization of the resulting amide in the presence of KOH. The c
- Arustamyan, Zh. S.,Margaryan,Aghekyan,Panosyan,Muradyan,Tumajyan
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p. 195 - 202
(2021/04/02)
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- Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease
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In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 μM; BChE IC50 = 14.05 ± 0.10 μM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 μM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 μM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid β1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.
- Chittiboyina, Amar G.,Doerksen, Robert J.,Modi, Gyan,Nayak, Prasanta Kumar,Pandey, Amruta,Pandey, Pankaj,Priya, Khushbu,Rai, Geeta,Shankar, Gauri,Singh, Yash Pal,Tej, Gullanki Naga Venkata Charan,Vishwakarma, Swati
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- Discovery of 5-naphthylidene-2,4-thiazolidinedione derivatives as selective HDAC8 inhibitors and evaluation of their cytotoxic effects in leukemic cell lines
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Histone deacetylases (HDACs) are being explored as a therapeutic target for interventions in different types of cancer. HDAC8 is a class I HDAC that is implicated as a therapeutic target in various indication areas, including different types of cancer and particularly childhood neuroblastoma. Most previously described HDAC8-selective inhibitors contain a hydroxamate function as zinc binding group (ZBG) to confer potency. However, hydroxamate class HDAC inhibitors have raised increasing concerns about their mutagenic character. Therefore, non-hydroxamate based inhibitors could prove to be safer than hydroxamates. In the present work, a series of novel 5-naphthylidene-2,4-thiazolidinedione was designed and evaluated as potential antiproliferative agents targeting selectively HDAC8 enzyme. Eleven novel derivatives were synthesized, purified and characterized by spectroscopic techniques. Compounds 3k and 3h was found to be most potent selective inhibitors of HDAC8 with IC50 values of 2.7 μM and 6.3 μM respectively. 3a to 3i was found to be most cytotoxic in leukemic cell lines. 3a and 3 h both were found to induce apoptosis and cause cell cycle arrest in G2/M phase.
- J?nsch, Niklas,Meyer-Almes, F. J.,Mrowka, Piotr,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha
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- Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-H1299 cells
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Eight novel moxifloxacin (MXF) derivatives 4a-h were synthesized by functional modification of the N-5-Aza ring. Their growth inhibitory activities on human non-small lung cancer cell NCI-H1299 and A549 were evaluated by the MTT colorimetric assay. Based on the half inhibitory concentration (IC50) values, we determined that compounds 4b was the most efficacious derivative (IC50 = 2.56 ± 0.07 μM for NCI-H1299 and IC50 = 13.69 ± 0.70 μM for A549, respectively) that inhibited the proliferation of NCI-H1299 cells. Of these, Compound 4b (1 – cyclopropyl – 6 – fluoro – 8 – methoxy – 4 – oxo – 7 – ((4aS,7aS) – 1 – (2 – oxo – 2 – (p – tolylamino) ethyl) hexahydro – 1H – pyrrolo [3,4-b] pyridine – 6(2H)-yl) – 1,4 – dihydroquinoline – 3-carboxylic acid) showed good potency against the growth of NCI-H1299 cells and also selectivity on HUVEC cells (IC50 > 500 μM). The dose-response relationship of the characteristic morphological changes of NCI-H1299 cells induced by Compound 4b was confirmed by AO/EB fluorescent staining. Furthermore, Compound 4b triggered apoptosis of NCI-H1299 in a concentration-dependent manner and arrested cells in the G0/G1 phase. These data indicate that the N-(p-tolyl)propanamide functionalized N-5-Aza ring of moxifloxacin may be a promising lead compound and candidate for the development of new agents against non-small-cell lung cancer.
- Yu, Fangmiao,Zhang, Zhuangwei,Li, Wei,Tian, Hengqun,Xu, Jun,Bao, Yongzhong
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supporting information
(2020/04/10)
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- Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation
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Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 – 9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 – 28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 – 104.2 μM) and human fibroblasts (HS27) (CC50 – 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.
- Aguilera, Renato J.,Choe, Jun-yong,Henze Macias, Luca,Hess, Jessica D.,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Schweipert, Markus,Tilekar, Kalpana,Upadhyay, Neha,J?nsch, Niklas
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- A Library of Thiazolidin-4-one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt To Discover Novel Antidiabetic Agents
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Protein tyrosine phosphatase 1B (PTP1B) is an important target for the treatment of diabetes. A series of thiazolidin-4-one derivatives 8–22 was designed, synthesized and investigated as PTP1B inhibitors. The new molecules inhibited PTP1B with IC50 values in the micromolar range. 5-(Furan-2-ylmethylene)-2-(4-nitrophenylimino)thiazolidin-4-one (17) exhibited potency with a competitive type of enzyme inhibition. structure–activity relationship studies revealed various structural facets important for the potency of these analogues. The findings revealed a requirement for a nitro group-including hydrophobic heteroaryl ring for PTP1B inhibition. Molecular docking studies afforded good correlation with experimental results. H-bonding and π–π interactions were responsible for optimal binding and effective stabilization of virtual protein-ligand complexes. Furthermore, in-silico pharmacokinetic properties of test compounds predicted their drug-like characteristics for potential oral use as antidiabetic agents.Additionally, a binding site model demonstrating crucial pharmacophoric characteristics influencing potency and binding affinity of inhibitors has been proposed, which can be employed in the design of future potential PTP1B inhibitors.
- Patel, Ashish D.,Pasha, Thopallada Y.,Lunagariya, Paras,Shah, Umang,Bhambharoliya, Tushar,Tripathi, Rati K. P.
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p. 1229 - 1242
(2020/06/08)
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- Synthesis, characterization, molecular docking, and biological activities of coumarin–1,2,3-triazole-acetamide hybrid derivatives
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Coumarins and their derivatives are receiving increasing attention due to numerous biochemical and pharmacological applications. In this study, a series of novel coumarin–1,2,3-triazole-acetamide hybrids was tested against some metabolic enzymes including α-glycosidase (α-Gly), α-amylase (α-Amy), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), human carbonic anhydrase I (hCA I), and hCA II. The new coumarin–1,2,3-triazole-acetamide hybrids showed Ki values in the range of 483.50–1,243.04 nM against hCA I, 508.55–1,284.36 nM against hCA II, 24.85–132.85 nM against AChE, 27.17–1,104.36 nM against BChE,?590.42–1,104.36 nM against α-Gly,?and 55.38–128.63 nM against α-Amy. The novel coumarin–1,2,3-triazole-acetamide hybrids had effective inhibition profiles against all tested metabolic enzymes. Also, due to the enzyme inhibitory effects of the new hybrids, they are potential drug candidates to treat diseases such as epilepsy, glaucoma, type-2 diabetes mellitus (T2DM), Alzheimer's disease (AD), and leukemia. Additionally, these inhibition effects were compared with standard enzyme inhibitors like acetazolamide (for hCA I and II), tacrine (for AChE and BChE), and acarbose (for α-Gly and α-Amy). Also, those coumarin–1,2,3-triazole-acetamide hybrids with the best inhibition score were docked into the active site of the indicated metabolic enzymes.
- Sepehri, Nima,Mohammadi-Khanaposhtani, Maryam,Asemanipoor, Nafise,Hosseini, Samanesadat,Biglar, Mahmood,Larijani, Bagher,Mahdavi, Mohammad,Hamedifar, Haleh,Taslimi, Parham,Sadeghian, Nastaran,Gulcin, Ilhami
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- Structure guided design and synthesis of furyl thiazolidinedione derivatives as inhibitors of GLUT 1 and GLUT 4, and evaluation of their anti-leukemic potential
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Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital ro
- Aguilera, Renato J.,Choe, Jun-yong,Hess, Jessica D.,Iancu, Cristina V.,Macias, Lucasantiago Henze,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Tilekar, Kalpana,Upadhyay, Neha
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- Design and synthesis of novel pyridazine N-aryl acetamides: In-vitro evaluation of α-glucosidase inhibition, docking, and kinetic studies
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We herein applied the four step-synthetic route to prepare the pyridazine core attached to the various N-aryl acetamides. By this approach, a new series of pyridazine-based compounds were synthesized, characterized and evaluated for their activities against α-glucosidase enzyme. In-vitro α-glucosidase assay established that twelve compounds are more potent than acarbose. Compound 7a inhibited α-glucosidase with the IC50 value of 70.1 μM. The most potent compounds showed no cytotoxicity against HDF cell line. Molecular docking and kinetic studies were performed to determine the modes of interaction and inhibition, respectively.
- Faramarzi, Mohammad Ali,Firoozpour, Loghman,Foroumadi, Alireza,Moghimi, Setareh,Mojtabavi, Somayeh,Sadat Ebrahimi, Seyed Esmaeil,Safari, Fatemeh,Salarinejad, Somayeh,Toolabi, Mahsa
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- Efficient synthesis, biological evaluation, and docking study of isatin based derivatives as caspase inhibitors
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ABTRACT: In this paper, a new series of isatin-sulphonamide based derivatives were designed, synthesised and evaluated as caspase inhibitors. The compounds containing 1-(pyrrolidinyl)sulphonyl and 2-(phenoxymethyl)pyrrolidin-1-yl)sulphonyl substitution at C5 position of isatin core exhibited better results compared to unsubstituted derivatives. According to the results of caspase inhibitory activity, compound 20d showed moderate inhibitory activity against caspase-3 and ?7 in?vitro compared to Ac-DEVD-CHO (IC50 = 0.016 ± 0.002 μM). Among the studied compounds, some active inhibitors with IC50s in the range of 2.33–116.91 μM were identified. The activity of compound 20d was rationalised by the molecular modelling studies exhibiting the additional van der Waals interaction of N-phenylacetamide substitution along with efficacious T-shaped π-π and pi-cation interactions. The introduction of compound 20d with good caspase inhibitory activity will help researchers to find more potent agents.
- Firoozpour, Loghman,Gao, Lixin,Moghimi, Setareh,Pasalar, Parvin,Davoodi, Jamshid,Wang, Ming-Wei,Rezaei, Zahra,Dadgar, Armin,Yahyavi, Hoda,Amanlou, Massoud,Foroumadi, Alireza
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p. 1674 - 1684
(2020/09/02)
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- Development of triazolothiadiazine derivatives as highly potent tubulin polymerization inhibitors: Structure-activity relationship, in vitro and in vivo study
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Based on our prior work, we reported the design, synthesis, and biological evaluation of fifty-two new triazolothiadiazine-based analogues of CA-4 and their preliminary structure-activity relationship. Among synthesized compounds, Iab was found to be the most potent derivative possessing IC50 values ranging from single-to double-digit nanomolar in vitro, and also exhibited excellent selectivity over the normal human embryonic kidney HEK-293 cells (IC50 > 100 μM). Further mechanistic studies revealed that Iab significantly blocked tubulin polymerization and disrupted the intracellular microtubule network of A549 cells. Moreover, Iab induced G2/M cell cycle arrest by regulation of p-cdc2 and cyclin B1 expressions, and caused cell apoptosis through up-regulating cleaved PARP and cleaved caspase-3 expressions, and down-regulating of Bcl-2. Importantly, in vivo, Iab effectively suppressed tumor growth of A549 lung cancers in a xenograft mouse model without obvious signs of toxicity, confirming its potential as a promising candidate for cancer treatment.
- Ma, Weifeng,Chen, Peng,Huo, Xiansen,Ma, Yufeng,Li, Yanhong,Diao, Pengcheng,Yang, Fang,Zheng, Shengquan,Hu, Mengjin,You, Wenwei,Zhao, Peiliang
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- Benzylidene thiazolidinediones: Synthesis, in vitro investigations of antiproliferative mechanisms and in vivo efficacy determination in combination with Imatinib
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Thiazolidinedione (TZD) has been an interesting scaffold due to its proven antidiabetic activity and encouraging findings in anticancer drug discovery. We synthesised benzylidene thiazolidinedione derivatives which exhibited excellent antiproliferative effects in chronic myeloid leukemic cells K562 and the most active compounds 3t and 3x had GI50 value of 0.9 and 0.23 μM respectively. Both the compound was found to arrest the growth of K562 cells in G0/G1 phase in a time and dose dependent manner. Further, western blot analysis revealed that 3t and 3x could also inhibit the expression of cell proliferation markers, PCNA and Cyclin D1 and compound 3x up-regulated apoptosis markers, cleaved PARP1 and activated caspase 3, which could be a possible mechanism for the excellent antiproliferative effects exhibited by these compounds. In vitro combination studies of 3t and 3x with Imatinib found to potentiate the antitumor effects of Imatinib. Further in vivo efficacy in K562 xenografts, of 3t and 3x alone and in combination with Imatinib was found to be promising and far better than control group and combination treatment was found to be more effective as compared to only Imatinib treated or test compound treated animals. Thus, our findings suggest that these compounds are promising antitumor agents and could help to enhance the anticancer effects of Imatinib and other tyrosine kinase inhibitors, when used in combination.
- Joshi, Hardik,Patil, Vijay,Tilekar, Kalpana,Upadhyay, Neha,Gota, Vikram,Ramaa
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supporting information
(2020/10/02)
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- Ultrasonic-Assisted Synthesis of Pyrazolo[3,4-d]pyrimidin-4-ol Tethered with 1,2,3-Triazoles and Their Anticancer Activity
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Abstract: In the presents work synthesis and characterization of new heterocyclic derivatives containing pyrazolo[3,4-d]pyrimidine linkage with 1,4-disubstituted-1,2,3-triazoles via methylene-oxy group. The selected synthesized compounds were tested for their in-vitro anticancer activity against various cancer cell lines. Synthesis of compounds was done under ultrasonic-assisted Huisgen 1,3-dipolar cycloaddition reaction with good yields. Some of the newly synthesized compounds demonstrated good to moderate anticancer activity, most of compounds shows activity against renal cancer cell lines.
- Bhatt, Tejal D.,Gojiya, Dinesh G.,Hadiyal, Sanjay D.,Joshi, Dr. Hitendra S.,Kapupara, Vimal H.,Prakash, L. Kalavadiya
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p. 803 - 813
(2020/10/29)
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- Design and synthesis of C-19 isosteviol derivatives as potent and highly selective antiproliferative agents
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Six series of novel isosteviol derivatives; modified in the C-19 position; were synthesized; and their antiproliferative activity was evaluated against three human cancer cell lines (HCT-116; BEL-7402; HepG2) and the human L02 normal cell line in vitro. M
- Luan, Tian,Cao, Li-Hua,Deng, Hao,Shen, Qing-Kun,Tian, Yu-Shun,Quan, Zhe-Shan
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- Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy
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Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells’ ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
- Sonawane, Vinay,Mohd Siddique, Mohd Usman,Jadav, Surender Singh,Sinha, Barij Nayan,Jayaprakash, Venkatesan,Chaudhuri, Bhabatosh
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p. 115 - 132
(2019/01/23)
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- Design, synthesis, and biological evaluation of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives as androgen receptor antagonists
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Androgen receptor (AR) signaling is often activated in prostate cancer (PCa) cells, and blockage of this signaling by AR antagonists is an important strategy in PCa therapy. In this study, we designed and synthesized a series of 2-(5-methyl-1H-pyrazol-1-y
- Dong, Junze,Zhang, Jingya,Li, Zilu,Asnake, Solomon,Zhang, Daoguang,Olsson, Per-Erik,Zhao, Guisen
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p. 380 - 386
(2019/01/30)
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- Synthesis, In Vitro Biological Screening, and In Silico Computational Studies of Some Novel Imidazole-2-thiol Derivatives
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Substituted imidazole analogues 2-((5-acetyl-4-methyl-1-phenyl-1H-imidazole-2-yl)thio)-N-phenylacetamides (3a–3m) have been synthesized from 1-[1-(phenyl)-2-mercapto-4-methyl-1H-imidazol-5-yl]-ethanone (1a–1e) and 2-chloro-N-phenylacetamide (2a–2i) in the
- Daraji, Drashti G.,Patel, Kinjal D.,Patel, Hitesh D.,Rajani, Dhanji P.
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p. 539 - 551
(2018/12/13)
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- CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity and cisplatin resistance
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Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in ‘suspension’ for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents. With live cell-based assays, quinazolinones 9i/9b were found to be selective CYP1A1/CYP1B1 inhibitors with IC50 values of 30/21 nM, and > 150-fold selectivity over CYP2/3 enzymes, whereas they were far less active using commercially-available CYP1A1/CYP1B1 microsomal enzymes (IC50, >10/1.3–1.7 μM). Compound 9i prevented CYP1A1-mediated benzo[a]pyrene-toxicity in normal fibroblasts whereas 9b completely reversed cisplatin resistance in PC-3/prostate, COR-L23/lung, MIAPaCa-2/pancreatic and LS174T/colon cancer cells, underlining the human-cell-assays’ potential. Our results indicate that the most potent CYP1A1/CYP1B1 inhibitors would not have been identified if one had relied merely on microsomal enzymes.
- Sonawane, Vinay R.,Siddique, Mohd Usman Mohd,Gatchie, Linda,Williams, Ibidapo S.,Bharate, Sandip B.,Jayaprakash, Venkatesan,Sinha, Barij N.,Chaudhuri, Bhabatosh
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p. 177 - 194
(2019/02/27)
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- Halogen-substituted triazolethioacetamides as a potent skeleton for the development of metallo-β-lactamase inhibitors
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Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MβLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC50 value range of 0.032–15.64 μM except 7. The chlorine substituted compounds (1, 2 and 3) inhibited NDM-1 with an IC50 value of less than 0.96 μM, and the fluorine substituted 12 and 13 inhibited VIM-2 with IC50 values of 38.9 and 2.8 μM, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that 9 and 13 are mixed inhibitors for ImiS with Ki values of 0.074 and 0.27μM using imipenem as the substrate. Docking studies showed that 1 and 9, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.
- Zhang, Yilin,Yan, Yong,Liang, Lufan,Jiefeng,Wang, Xuejun,Li, Li,Yang, Kewu
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- Synthesis, Antimicrobial Evaluation, and Docking Studies of Substituted Acetylphenoxymethyl-triazolyl-N-phenylacetamides
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A series of molecules containing acetylphenoxymethyl, triazole, and N-phenylacetamide moieties were synthesized via the click chemistry approach. All the synthesized compounds were screened for their antimicrobial activities in vitro. The synthesized compounds 8a, 8b, 8m, and 8n showed better activities. We further performed exploratory docking studies to gain some insight regarding the molecular mechanism of antibacterial action of these compounds that could guide further structure-activity relationship (SAR) studies. We examined the interaction of the most active compound with DNA gyrase (pdb id:1KZN). Based on antimicrobial and docking studies, the compounds 8a, 8b, 8m, and 8n were identified as potential antimicrobial agents.
- Phatak, Pramod S.,Sathe, Bhaurao P.,Dhumal, Sambhaji T.,Rehman, Naziya N. M. A.,Dixit, Prashant P.,Khedkar, Vijay M.,Haval, Kishan P.
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- Substituted Aminoacetamides as Novel Leads for Malaria Treatment
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Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.
- Norcross, Neil R.,Wilson, Caroline,Baraga?a, Beatriz,Hallyburton, Irene,Osuna-Cabello, Maria,Norval, Suzanne,Riley, Jennifer,Fletcher, Daniel,Sinden, Robert,Delves, Michael,Ruecker, Andrea,Duffy, Sandra,Meister, Stephan,Antonova-Koch, Yevgeniya,Crespo, Benigno,de Cózar, Cristina,Sanz, Laura M.,Gamo, Francisco Javier,Avery, Vicky M.,Frearson, Julie A.,Gray, David W.,Fairlamb, Alan H.,Winzeler, Elizabeth A.,Waterson, David,Campbell, Simon F.,Willis, Paul A.,Read, Kevin D.,Gilbert, Ian H.
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supporting information
p. 1329 - 1335
(2019/07/17)
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- Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries
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Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification.
- Jing, Lanlan,Wu, Gaochan,Hao, Xia,Olotu, Fisayo A.,Kang, Dongwei,Chen, Chin Ho,Lee, Kuo-Hsiung,Soliman, Mahmoud E.S.,Liu, Xinyong,Song, Yuning,Zhan, Peng
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- A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding interactions
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The Forkhead boX M1 (FOXM1) protein is an essential transcription factor required for the normal activation of human cell cycle. However, increasing evidence supports a correlation between FOXM1 overexpression and the onset of several types of cancer. Based on a previously reported molecular modeling and molecular dynamics simulations (MD) study, we hypothesized the role of an essential halogen-bonding interaction between the 4-fluorophenyl group in the forkhead domain inhibitor-6 (FDI-6) and an Arg297 residue inside the FOXM1-DNA binding domain (DBD). To prove the importance of this binding interaction, we synthesized and screened ten FDI-6 derivatives possessing different groups at the 4-fluorophenyl position of the lead molecule. Briefly, we found that derivatives possessing a 4-chlorophenyl, 4-bromophenyl, or a 4-iodophenyl group, were equipotent to the original 4-fluorophenyl moiety present in FDI-6, whereas derivatives without this 4-halogen moiety were inactive. We also observed that positional isomers in which the halogen was relocated to positions 2- or 3- on the phenyl group were significantly less active. These results provide evidence to support the essential role of a 4-halophenyl bonding interaction, with the Arg297 residue in the FOXM1-DBD, to exert inhibition of transcriptional activity.
- Tabatabaei Dakhili, Seyed Amirhossein,Pérez, David J.,Gopal, Keshav,Tabatabaei Dakhili, Seyed Yasin,Ussher, John R.,Velázquez-Martínez, Carlos A.
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supporting information
(2019/10/28)
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- Coumarin and 3,4-dihydroquinolinone derivatives: Synthesis, antidepressant activity, and molecular docking studies
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Background: Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. Methods: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. Results: Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. Conclusion: Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.
- Wang, Shi-Ben,Liu, Hui,Li, Guang-Yong,Li, Jun,Li, Xiao-Jing,Lei, Kang,Wei, Li-Chao,Quan, Zhe-Shan,Wang, Xue-Kun,Liu, Ren-Min
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p. 1244 - 1252
(2019/11/02)
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- Substituted chloroacetamides as potential cancer stem cell inhibitors: Synthesis and biological evaluation
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Cancer kills, irrespective of geographical and cultural origin. Novel modalities for treating cancer are desperately needed. Cancer stem cells (CSCs), main culprits behind chemoresistance and tumor relapse, are one of the few logical choices. Herein, we r
- Athavale, Maithili,Kharkar, Prashant S.,Padhariya, Komal N.,Srivastava, Sangeeta
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- Synthesis and biological evaluation of novel N-aryl-ω-(benzoazol-2-yl)-sulfanylalkanamides as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1B
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α-Glucosidase is known to catalyze the digestion of carbohydrates and release free glucose into the digestive tract. Protein tyrosine phosphatase 1B (PTP1B) is engaged in the dephosphorylation of the insulin receptor and regulation of insulin sensitivity.
- Wang, Mei-Yan,Cheng, Xian-Chao,Chen, Xiu-Bo,Li, Yu,Zang, Lan-Lan,Duan, Yu-Qing,Chen, Ming-Zhu,Yu, Peng,Sun, Hua,Wang, Run-Ling
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p. 1647 - 1656
(2018/09/10)
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- Design, synthesis, and SAR of novel 2-glycinamide cyclohexyl sulfonamide derivatives against botrytis cinerea
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N-(2-trifluoromethyl-4-chlorophenyl)-2-oxocyclohexyl sulfonamide (chesulfamide) is in the limelight as a novel fungicide, and has fungicidal activity against Botrytis cinerea. For exploring more novel structures, 33 new compounds were synthesized by N-alkylation and acid–amine coupling reactions with chesulfamide as the core moiety, and their structures were characterized and established by 1H-NMR, 13C-NMR, MS, and elemental analysis. The structure of (1R,2S)-2-(2-(N-(4-chloro-2-trifluoromethylphenyl)sulfamoyl)-cyclohexylamino)-N-(2-trifluoromethylphenyl) acetamide (II-19) was defined by X-ray single crystal diffraction. The in vivo and in vitro fungicidal activities against B. cinerea were evaluated. The bioassay results of mycelial growth demonstrated that most compounds exhibited excellent inhibitory activity against B. cinerea at 50 μg mL?1, and 7 compounds showed lower EC50 values than boscalid (EC50 = 4.46 μg mL?1) against B. cinerea (CY-09). In cucumber pot experiment, the inhibitory rates of four compounds (II-4, II-5, II-12, and II-13) against B. cinerea were 90.48, 93.45, 92.86, and 91.07, which were better than cyprodinil (88.69%), the best performing of all controls. In tomato pot experiment, the control efficacy of two analogs (II-8 and II-15) were 87.98 and 87.97% at 200 μg mL?1, which were significantly higher than boscalid (78.10%). Most compounds have an excellent fungicidal effect on B. cinerea, with potential as a lead compound for developing new pesticides.
- Cai, Nan,Liu, Caixiu,Feng, Zhihui,Li, Xinghai,Qi, Zhiqiu,Ji, Mingshan,Qin, Peiwen,Ahmed, Wasim,Cui, Zining
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- Design, synthesis, docking study, α-glucosidase inhibition, and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes
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A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC50 = 80.0 ± 2.0–383.1 ± 2.0 μM against yeast α-glucosidase, when compared to the standard drug acarbose (IC50 = 750.0 ± 1.5 μM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC50 = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a Ki of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.
- Mohammadi-Khanaposhtani, Maryam,Rezaei, Sepideh,Khalifeh, Reza,Imanparast, Somaye,Faramarzi, Mohammad Ali,Bahadorikhalili, Saeed,Safavi, Malihe,Bandarian, Fatemeh,Nasli Esfahani, Ensieh,Mahdavi, Mohammad,Larijani, Bagher
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p. 288 - 295
(2018/07/06)
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- SULFONAMIDE OR AMIDE COMPOUNDS, COMPOSITIONS AND METHODS FOR THE PROPHYLAXIS AND/OR TREATMENT OF AUTOIMMUNE, INFLAMMATION OR INFECTION RELATED DISORDERS
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The present invention related to novel sulfonamides or amides as TLR-4 antagonists, and pharmaceutical formulations containing the same and the methods of use thereof. Uses of the present novel sulfonamides or amides include, but are not limited to, the prophylaxis and/or treatment of autoimmune, inflammation, or infection related disorders.
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Paragraph 0101; 0102; 0103; 0104
(2018/09/19)
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- 1,3-disubstituted pyrazole derivative as well as preparation method and application thereof
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The invention discloses a 1,3-disubstituted pyrazole derivative as well as a preparation method and application thereof. The compound has a structure shown as a general formula (I). The invention further provides a preparation method of the compounds and
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Paragraph 0078; 0079; 0080; 0082
(2018/03/24)
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- 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones, and synthesis method and application thereof
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The invention discloses 1,3-dimethyl-7-substituted-quinazolinyl-2,4-diones. The structural general formula of the compounds is disclosed in the specification, wherein R1 is hydrogen or ethyl; and R2 is a benzene ring, benzene ring derivative, heterocyclic ring or aliphatic hydrocarbon. Part of compounds have favorable inhibiting activities for Candida albicans, Aspergillus flavus, Torula histolytica and Aspergillus fumigatus. The compounds have obvious inhibiting activities for chitin synthetase, have favorable antibacterial effects, and can be used for preparing drugs for anti-pathogenic microorganisms.
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Paragraph 0056; 0057; 0058; 0059; 0060; 0073; 0074
(2017/07/31)
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- Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes
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The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTr
- Banno, Yoshihiro,Sasaki, Shigekazu,Kamata, Makoto,Kunitomo, Jun,Miyamoto, Yasufumi,Abe, Hidenori,Taya, Naohiro,Oi, Satoru,Watanabe, Masanori,Urushibara, Tomoko,Hazama, Masatoshi,Niwa, Shin-ichi,Miyamoto, Saku,Horinouchi, Akira,Kuroshima, Ken-ichi,Amano, Nobuyuki,Matsumoto, Shin-ichi,Matsunaga, Shinichiro
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p. 5995 - 6006
(2017/10/10)
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- [6,6] FUSED BICYCLIC HDAC8 INHIBITORS
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The present invention is directed to compounds of Formula I: and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers or thereof, wherein R1, R2, R2', L, X, W, Y1,Y2,
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Paragraph 00353
(2019/08/15)
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- Synthesis, in?vitro evaluation and molecular docking studies of novel triazine-triazole derivatives as potential α-glucosidase inhibitors
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A novel series of triazine-triazole derivatives 7a–7m were synthesized, characterized by1H NMR and evaluated for their α-glucosidase inhibitory activity. All the synthesized compounds displayed potent α-glucosidase inhibitory activity with IC50range of 11.63?±?0.15 to 37.44?±?0.35?μM, when compared to the standard drug acarbose (IC50?=?817.38?±?6.27?μM). Among the series, compound 7i (IC50?=?11.63?±?0.15?μM) bearing 2,5-dichloro substitution at phenyl ring, represented the most potent α-glucosidase inhibitory activity. Molecular docking studies of the most active compounds with the homology modelled α-glucosidase were also performed to explore the possible inhibitory mechanism. Our studies shown that these triazine-triazole derivatives are a new class of α-glucosidase inhibitors.
- Wang, Guangcheng,Peng, Zhiyun,Wang, Jing,Li, Xin,Li, Juan
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p. 423 - 429
(2016/10/03)
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- Synthesis, molecular docking and α-glucosidase inhibition of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides
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A novel series of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides 5a–5q have been synthesized and evaluated for their α-glucosidase inhibitory activity. All newly synthesized compounds exhibited potent α-glucosidase inhibitory activity in the range of IC50?=?12.46?±?0.13–72.68?±?0.20?μM, when compared to the standard drug acarbose (IC50?=?817.38?±?6.27?μM). Among the series, compound 5j (12.46?±?0.13?μM) with strong electron-withdrawing nitro group on the arylacetamide moiety was identified as the most potent inhibitor of α-glucosidase. Molecular docking study was carried out to explore the binding interactions of these compounds with α-glucosidase. Our study identifies a novel series of potent α-glucosidase inhibitors for further investigation.
- Wang, Guangcheng,Li, Xin,Wang, Jing,Xie, Zhenzhen,Li, Luyao,Chen, Ming,Chen, Shan,Peng, Yaping
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p. 1115 - 1118
(2017/06/19)
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- Amides myricetin derivative and preparation method and application thereof
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The invention discloses an amides myricetin derivative and a preparation method and application thereof. The general molecular formula (I) of the amides myricetin derivative is shown in the instruction, specifically, R is alkyl, benzyl, substituted phenyl
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Paragraph 0015
(2017/05/26)
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- Design, synthesis and antiproliferative evaluation of novel disulfides containing 1,3,4-thiadiazole moiety
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A series of novel disulfides containing 1,3,4-thiadiazole moiety were designed, synthesized, and the structures of all products were identified by spectral data (IR, NMR, and high resolution (HR)-MS). Their in vitro antiproliferative activities were evalu
- Zhang, Shuai,Liu, Xiao-Jia,Tang, Rui,Wang, Hai-Xin,Liu, Hai-Ying,Liu, Yu-Ming,Chen, Bao-Quan
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p. 950 - 958
(2018/10/31)
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- IMMUNOREGULATORY AGENTS
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Compounds that modulate the oxidoreductase enzyme indoleamine 2,3- dioxygenase, and compositions containing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases,
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Paragraph 0242; 0483
(2016/06/01)
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- Containing amide group, a benzenesulfonyl amine compound and its preparation and use
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The invention discloses benzsulfamide compounds containing amido group, and preparation and application thereof. The structural formula of the benzsulfamide compounds containing amido group is disclosed as Formula I, wherein R1 is selected from F, Cl and
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Paragraph 0016; 0017; 0018
(2016/10/08)
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