- Structure-guided design of thiazolidine derivatives as mycobacterium tuberculosis pantothenate synthetase inhibitors
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The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis (Mtb) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of Mtb PS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy-based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC50) value of (1.12±0.12) μM. These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC50 value of 350 nM and an Mtb minimum inhibitory concentration (MIC) of 1.55 μM. Some of these compounds also showed good activity against dormant Mtb cells. Let sleeping cells lie: Mycobacterium tuberculosis pantothenate synthetase (Mtb PS) has become a target for new therapeutics to treat tuberculosis. Nanomolar thiazolidine inhibitors of Mtb PS were developed by rational inhibitor design involving modelling, in vitro screening and optimisation. Hit expansion of the lead by synthesis led to an improved inhibitor with an IC50 value of 350 nM and an Mtb MIC value of 1.55 μM. Some of these compounds also showed good activity against dormant Mtb cells.
- Devi, Parthiban Brindha,Samala, Ganesh,Sridevi, Jonnalagadda Padma,Saxena, Shalini,Alvala, Mallika,Salina, Elena G.,Sriram, Dharmarajan,Yogeeswari, Perumal
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- In search for multi-target ligands as potential agents for diabetes mellitus and its complications—a structure-activity relationship study on inhibitors of aldose reductase and protein tyrosine phosphatase 1b
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Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.
- Adornato, Ilenia,Cappiello, Mario,Del Corso, Antonella,Genovese, Massimo,Maccari, Rosanna,Moschini, Roberta,Na?, Alexandra,Nesi, Ilaria,Nguyen, Trung Ngoc,Ottanà, Rosaria,Paoli, Paolo,Wolber, Gerhard
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- 5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxothiazolidin-3-yl)alkancarboxylic Acids as Antimicrobial Agents: Synthesis, biological evaluation, and molecular docking studies
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Background: Infectious diseases symbolize a global consequential strain on public health security and impact on the socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in crucial need for the discovery and development of novel entity for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using classical methods of organic synthesis. Results: All 20 synthesized compounds showed antibacterial activity against eight Gram-positive and Gram-negative bacterial species. It should be mentioned that all compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Furthermore, 18 compounds appeared to be more potent than streptomycin against Staphylococcus aureus, Enterobacter cloacae, Pseudomonas aeruginosa, Listeria monocytogenes, and Escherichia coli. Three the most active compounds 4h, 5b, and 5g appeared to be more potent against MRSA than ampicillin, while streptomycin did not show any bactericidal activity. All three compounds displayed better activity also against resistant strains P. aeruginosa and E. coli than ampicillin. Furthermore, all compounds were able to inhibit biofilm formation 2- to 4-times more than both reference drugs. Compounds were evaluated also for their antifungal activity against eight species. The evaluation revealed that all compounds exhibited antifungal activity better than the reference drugs bifonazole and ketoconazole. Molecular docking studies on antibacterial and antifungal targets were performed in order to elucidate the mechanism of antibacterial activity of synthesized compounds. Conclusion: All tested compounds showed good antibacterial and antifungal activity better than that of reference drugs and three the most active compounds could consider as lead compounds for the development of new more potent agents.
- Ciric, Ana,Geronikaki, Athina,Glamoclija, Jasmina,Horishny, Volodymyr,Kartsev, Victor,Matiychuk, Vasyl,Petrou, Anthi,Sokovic, Marina
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- Discovery of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups as potential PTP1B inhibitors
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Two series of 1,3-diphenyl-1H-pyrazole derivatives containing rhodanine-3-alkanoic acid groups were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, IIIv was found to have the best in vitro inhibition activity against PTP1B (IC50 = 0.67 ± 0.09 μM) and the best selectivity (9-fold) between PTP1B and T-cell protein tyrosine phosphatase (TCPTP). Molecular docking studies demonstrated that compounds IIIm, IIIv and IVg could occupy simultaneously at both the catalytic site and the adjacent pTyr binding site. These results provide novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.
- Sun, Liangpeng,Wang, Peipei,Xu, Lili,Gao, Lixin,Li, Jia,Piao, Huri
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p. 1187 - 1193
(2019/03/26)
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- Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids
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A series of rhodanine 3-carboxyalkanoic acid derivatives possessing 4′-(N,N-dialkyl-amino or diphenylamino)-benzylidene moiety as a substituent at the C-5 position were synthesised and their antibacterial activity was screened. All the rhodanine derivatives showed bacteriostatic or bactericidal activity to the reference gram-positive bacterial strains, but lack of activity to the reference Gram-negative bacterial strains and yeast strains was observed.
- Tejchman, Waldemar,Korona-Glowniak, Izabela,Malm, Anna,Zylewski, Marek,Suder, Piotr
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p. 1316 - 1324
(2017/05/04)
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- Spectral Characteristic and Preliminary Anticancer Activity in vitro of Selected Rhodanine-3-carboxylic Acids Derivatives
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Selected rhodanine-3-carboxylic acids derivatives were synthesized to determine the influence of the structure and the length of the linker between the carboxyl group and the nitrogen atom (N-3) in the 2-thioxo-4-thiazolidinone ring on their activity, monitored via interactions with human serum albumin. Based on fluorescence studies, we concluded that the length of the linker has a limited impact on these interactions. Additionally, we proposed the static mechanism of quenching for all the tested compounds. These derivatives seem to possess an anticancer activity in the nanomolar range with 3 as the most potent compound in both A2780 and A2780cisR cell lines.
- Stawoska, Iwona,Tejchman, Waldemar,Mazuryk, Olga,Ly?ka, Antonín,Nowak-Sliwinska, Patrycja,?es?awska, Ewa,Nitek, Wojciech,Kania, Agnieszka
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p. 2889 - 2897
(2017/09/25)
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- In Silico Driven Design and Synthesis of Rhodanine Derivatives as Novel Antibacterials Targeting the Enoyl Reductase InhA
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Here, we report on the design, synthesis, and biological evaluation of 4-thiazolidinone (rhodanine) derivatives targeting Mycobacterial tuberculosis (Mtb) trans-2-enoyl-acyl carrier protein reductase (InhA). Compounds having bulky aromatic substituents at position 5 and a tryptophan residue at position N-3 of the rhodanine ring were the most active against InhA, with IC50 values ranging from 2.7 to 30 μM. The experimental data showed consistent correlations with computational studies. Their antimicrobial activity was assessed against Mycobacterium marinum (Mm) (a model for Mtb), Pseudomonas aeruginosa (Pa), Legionella pneumophila (Lp), and Enterococcus faecalis (Ef) by using anti-infective, antivirulence, and antibiotic assays. Nineteen out of 34 compounds reduced Mm virulence at 10 μM. 33 exhibited promising antibiotic activity against Mm with a MIC of 0.21 μM and showed up to 89% reduction of Lp growth in an anti-infective assay at 30 μM. 32 showed high antibiotic activity against Ef, with a MIC of 0.57 μM.
- Slepikas, Liudas,Chiriano, Gianpaolo,Perozzo, Remo,Tardy, Sébastien,Kranjc, Agata,Patthey-Vuadens, Ophélie,Ouertatani-Sakouhi, Hajer,Kicka, Sébastien,Harrison, Christopher F.,Scrignari, Tiziana,Perron, Karl,Hilbi, Hubert,Soldati, Thierry,Cosson, Pierre,Tarasevicius, Eduardas,Scapozza, Leonardo
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p. 10917 - 10928
(2016/12/30)
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- The Crystal Structures of Three Rhodanine-3-Carboxylic Acids
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Abstract: The rhodanine derivatives show various pharmacological activities. Rhodanine-3-carboxylic acids can be used as the substrates in various synthesis of compounds containing rhodanine-3-carboxyalkyl moiety. In this paper new crystal structures of rhodanine-3-acetic acid and its two homologues, i.e. rhodanine-3-propionic acid and rhodanine-3-butyric acid, are reported. The relationship between the length of the alkyl chain and the geometry of these molecules was studied. The crystal network is dominated by strong hydrogen bonds O–H···O formed by the carboxyl groups. Additionally, weak C–H···O and C–H···S contacts are observed. Graphical Abstract: To study the difference in intermolecular interactions of rhodanine-3-carboxylic acid, three crystal structures were determined by X-ray diffraction method. The crystal network in all studied structures is built of homosynthons and stabilized by weak C–H···O and C–H···S contacts.[Figure not available: see fulltext.]
- Tejchman, Waldemar,Skórska-Stania, Agnieszka,?es?awska, Ewa
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p. 181 - 187
(2016/05/02)
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- Novel tetrazoloquinoline-rhodanine conjugates: Highly efficient synthesis and biological evaluation
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In search of new active molecules against Mycobacterium tuberculosis (MTB) H37Ra and Mycobacterium bovis BCG, a small focused library of rhodanine incorporated tetrazoloquinoline has been efficiently synthesized by using [HDBU][HSO4] acidic ionic liquid. The compound 3c found to be promising inhibitor of MTB H37Ra and M. bovis BCG characterized by lower MIC values 4.5 and 2.0 μg/mL, respectively. The active compounds were further tested for cytotoxicity against HeLa, THP-1, A549 and PANC-1 cell lines using MTT assay and showed no significant cytotoxic activity at the maximum concentration evaluated. Again, the synthesized compounds were found to have potential antifungal activity. Furthermore, to rationalize the observed biological activity data, the molecular docking study also been carried out against a potential target Zmp1 enzyme of MTB H37Ra, which revealed a significant correlation between the binding score and biological activity for these compounds. The results of in vitro and in silico study suggest that these compounds possess ideal structural requirement for the further development of novel therapeutic agents.
- Subhedar, Dnyaneshwar D.,Shaikh, Mubarak H.,Nawale, Laxman,Yeware, Amar,Sarkar, Dhiman,Khan, Firoz A. Kalam,Sangshetti, Jaiprakash N.,Shingate, Bapurao B.
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supporting information
p. 2278 - 2283
(2016/04/20)
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- Structure-Guided Design of Thiazolidine Derivatives as Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors
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The pantothenate biosynthetic pathway is essential for the persistent growth and virulence of Mycobacterium tuberculosis (Mtb) and one of the enzymes in the pathway, pantothenate synthetase (PS, EC: 6.3.2.1), encoded by the panC gene, has become an appropriate target for new therapeutics to treat tuberculosis. Herein, we report nanomolar thiazolidine inhibitors of MtbPS developed by a rational inhibitor design approach. The thiazolidine compounds were discovered by using energy-based pharmacophore modelling and subsequent in vitro screening, which resulted in compounds with a half maximal inhibitory concentration (IC50) value of (1.12±0.12)μM. These compounds were subsequently optimised by a combination of modelling and synthetic chemistry. Hit expansion of the lead by chemical synthesis led to an improved inhibitor with an IC50 value of 350nM and an Mtb minimum inhibitory concentration (MIC) of 1.55μM. Some of these compounds also showed good activity against dormant Mtb cells.
- Devi, Parthiban Brindha,Samala, Ganesh,Sridevi, Jonnalagadda Padma,Saxena, Shalini,Alvala, Mallika,Salina, Elena G.,Sriram, Dharmarajan,Yogeeswari, Perumal
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p. 2538 - 2547
(2015/08/24)
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- Toward the Discovery of Novel Anti-HIV Drugs. Second-Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti-HIV Activity: Synthesis, Structure-Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation
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A hit optimization protocol applied to the first nonnucleoside inhibitor of the ATPase activity of human DEAD-box RNA helicase DDX3 led to the design and synthesis of second-generation rhodanine derivatives with better inhibitory activity toward cellular DDX3 and HIV-1 replication. Additional DDX3 inhibitors were identified among triazine compounds. Biological data were rationalized in terms of structure-activity relationships and docking simulations. Antiviral activity and cytotoxicity of selected DDX3 inhibitors are reported and discussed. A thorough analysis confirmed human DDX3 as a valid anti-HIV target. The compounds described herein represent a significant advance in the pursuit of novel drugs that target HIV-1 host cofactors.
- Maga, Giovanni,Falchi, Federico,Radi, Marco,Botta, Lorenzo,Casaluce, Gianni,Bernardini, Martina,Irannejad, Hamid,Manetti, Fabrizio,Garbelli, Anna,Samuele, Alberta,Zanoli, Samantha,Este, Jose A.,Gonzalez, Emmanuel,Zucca, Elisa,Paolucci, Stefania,Baldanti, Fausto,DeRijck, Jan,Debyser, Zeger,Botta, Maurizio
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experimental part
p. 1371 - 1389
(2012/07/28)
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- COMPOUNDS WITH DDX3 INHIBITORY ACTIVITY AND USES THEREOF
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The present invention relates to the medical use of the compound of formula 1,2,3 or 4
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Page/Page column 149-150
(2011/04/25)
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