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Publication Date: 2006
Publication Name: Journal of Heterocyclic Chemistry
Research Interests:
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Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a... more
Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) ...
Publisher: ncbi.nlm.nih.gov
Publication Date: Jan 5, 2008
Publication Name: Proceedings of the National Academy of Sciences of the United States of America
Research Interests: Drug Discovery, Enzyme Inhibitors, Drug development, Folic acid, Multidisciplinary, and 12 moreMacromolecular X-Ray Crystallography, Crystal structure, Animals, Drug Resistance, Oxidoreductases, Drug Design, Enzyme, Trypanosoma Cruzi, Trypanocidal Agents, Protozoan Proteins, Leishmania Major, and Dihydrofolate Reductase
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Publication Date: 2008
Publication Name: European Journal of Medicinal Chemistry
Research Interests: Organic Chemistry, Kinetics, Modeling, Ovarian Cancer, Cell line, and 14 moreIn Vitro, Humans, European, Cytotoxic Activity, Molecular Model, Ovarian Carcinoma, Molecular Conformation, Cell Proliferation, Biological activity, Ovary, Chemical Synthesis, Antineoplastic Agents, Glutamic Acid, and aniline Compounds
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Publication Date: 2012
Publication Name: Journal of Medicinal Chemistry
Research Interests:
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Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one... more
Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one 2-[N-methyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines (1-31). The lead compound 1 was previously reported to be endowed with significant inhibition against hDHFR enzyme, with a Ki of 0.2 μM. Docking studies were performed on compound 1 and here reported to predict its binding conformation to human dihydrofolate reductase (hDHFR). All compounds (1-31) were assayed versus hDHFR and human thymidylate synthase (hTS). From the screening emerged that all compounds inhibited hDHFR with Ki values included between 0.2 and 11 μM, while only a few (6, 21, 24, 27, 29) showed great activity and selectivity towards hTS. Evaluation of the anticancer activity was performed by NCI, first against the three cell line panel, and only the most active compounds (17, 21, 24, 26, 27) were evaluated on a panel of 60 human tumor cell lines. Compound 21 was the most active against all cell lines with log GI50 equal to -5.49 and log LC50 equal to -4.19 and maintained significant percent of growth inhibition on seven cancer cell lines at the concentration of 1 μM. Compound 17 was the second most active and moreover showed interesting selectivity against some cell lines (Lung cancer: A549/ATCC, Melanoma: UACC-257, Ovarian Cancer: ovcar-8 and Renal cancer: RXF 393) at all concentration examined (100-0.01 μM).
Publication Date: 2014
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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It is also possible that your web browser is not configured or not able to display style sheets. In this case, although the visual presentation will be degraded, the site should continue to be functional. We recommend using the latest... more
It is also possible that your web browser is not configured or not able to display style sheets. In this case, although the visual presentation will be degraded, the site should continue to be functional. We recommend using the latest version of Microsoft or Mozilla web browser to ...
Publication Date: 2008
Publication Name: ChemInform
Research Interests:
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4-Substituted anilino imidazo[1,2-a] and triazolo[4,3-a]quinoxalines. Synthesis and evaluation of in vitro biological activitymore
by Paola Corona and Giuseppe Paglietti
Fifteen imidazo[1,2-a] and [1,2,4]triazolo[4,3-a]quinoxalines were prepared. These compounds bear at position 4 various substituents related to the moieties present in classical and non-classical antifolic agents. And we evaluated in... more
Fifteen imidazo[1,2-a] and [1,2,4]triazolo[4,3-a]quinoxalines were prepared. These compounds bear at position 4 various substituents related to the moieties present in classical and non-classical antifolic agents. And we evaluated in vitro antimicrobial, antiviral and antiproliferative activities. In particular, title compounds were evaluated in vitro against representative strains of Gram-positive and Gram-negative bacteria (S. aureus, Salmonella spp.), mycobacteria (M. fortuitum, M. smegmatis ATCC 19420 and
Publication Date: 2006
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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Publication Date: 2006
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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Two series of 1,6-dimethyl-3-phenoxymethylquinoxalin-2-ones and 1-benzyl-3-phenoxymethyl-7-trifluoromethylquinoxalin-2-ones, and a series of 2-benzyloxy-3-phenoxymethyl-7-trifluoromethylquinoxaline were synthesized. Their capability to... more
Two series of 1,6-dimethyl-3-phenoxymethylquinoxalin-2-ones and 1-benzyl-3-phenoxymethyl-7-trifluoromethylquinoxalin-2-ones, and a series of 2-benzyloxy-3-phenoxymethyl-7-trifluoromethylquinoxaline were synthesized. Their capability to restore/potentiate the antiproliferative activity of clinically useful drugs, such as doxorubicin (Doxo), vincristine (VCR) and etoposide (VP16), in drug-resistant human nasopharyngeal carcinoma KB cells (KB(WT), KB(MDR), KB(7D)and KB(V20C)) was evaluated. In vitro data show that many quinoxalin-2-ones and quinoxalines potentiate the antiproliferative activity of Doxo and VCR in tumor-derived MDR cell lines. In this series, 17a turned out to be the most potent quinoxaline derivative in potentiating the antiproliferative activity of doxorubicin and vincristine against KB(MDR) and KB(V20C) resistant cell lines, respectively.
Publication Date: 2006
Publication Name: Medicinal chemistry (Shāriqah (United Arab Emirates))
Research Interests:
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Collateral sensitivity to novel thymidylate synthase inhibitors correlates with folate cycle enzymes impairment in cisplatin-resistant human ovarian cancer cellsmore
by Paola Corona and Giuseppe Paglietti
Publication Date: 2009
Publication Name: European Journal of Pharmacology
Research Interests:
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by Paola Corona and Giuseppe Paglietti
As a follow up of an anti-Flaviviridae project, a new series of variously substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for biological activity. Compounds were tested in cell-based assays against viruses... more
As a follow up of an anti-Flaviviridae project, a new series of variously substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for biological activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Pestiviruses and Flaviviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae) as well as for cytotoxicity tests, run in parallel with antiviral assays,against MDBK, BHK and Vero 76 cells. In the series examined, new leads emerged against BVDV, CVB-2 and RSV. Compounds 11, 12, 17, 18, 24, 31 exhibited anti-BVDV activity in the concentration range 1.7-16 microM; among them, compound 17 was the most active, with an EC(50) = 1.7 microM. Compounds 18 and 21 were equally active against CVB-2, with EC(50) values of 7 - 8 microM, while the derivative 30 was active against RSV with EC(50)= 1 microM and represents a new lead compound.
Publication Date: 2010
Publication Name: Medicinal Chemistry
Research Interests: Medicinal Chemistry, DNA viruses, RNA viruses, Cercopithecus aethiops, Cell line, and 13 moreAnimals, Drug Design, Cattle, Medicinal, Microbial Sensitivity Tests, Molecular Conformation, Biological activity, Benzimidazoles, Structure activity Relationship, Cell Survival, Vero cells, Flaviviridae, and Antiviral Agents
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Quinoxaline chemistry. Part 11. 3-Phenyl-2 [phenoxy- and phenoxymethyl]-6(7) or 6,8-substituted quinoxalines and N-[4-(6(7)-substituted or 6,8-disubstituted-3-phenylquinoxalin-2-yl)hydroxy or hydroxymethyl]benzoylglutamates. Synthesis and evaluation of in vitro anticancer activity and enzymatic i...more
by Paola Corona and Giuseppe Paglietti
Twenty-four out of twenty-nine quinoxalines were selected at the National Cancer Institute, Bethesda, Md, USA, for in vitro anticancer screening. Among these, 10 derivatives exhibited high values of percent tumor growth inhibition at a... more
Twenty-four out of twenty-nine quinoxalines were selected at the National Cancer Institute, Bethesda, Md, USA, for in vitro anticancer screening. Among these, 10 derivatives exhibited high values of percent tumor growth inhibition at a concentration of 10(-4) M in all cancer cell lines. Four of these compounds maintained these values at 10(-5) M, whereas a certain number exhibited significant values of percent inhibition at the most diluted concentrations (10(-8)-10(-6) M). Inhibitory activity against dihydrofolate reductase (DHFR) (bovine and rat liver) was determined for the most active compounds. This test showed that this type of quinoxaline exhibited an appreciable activity in comparison with the previously described aza analogues. In the other test (Lactobacillus casei, thymidylate synthase (TS), human HTS) no or poor activity was detected in both series of compounds.
Publication Date: 1998
Publication Name: Il Farmaco
Research Interests:
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4-Substituted anilino imidazo[1,2-a] and triazolo[4,3-a]quinoxalines. Synthesis and evaluation of in vitro biological activitymore
by Paola Corona and Giuseppe Paglietti
Publication Date: 2006
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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Thirty quinoxalines bearing a substituted phenoxy or hydroxybenzoylglutamate group on position 2, a carboethoxy or carboxy group on position 3 and a trifluoromethyl group on position 6 or 7 of the heterocycle were prepared in order to... more
Thirty quinoxalines bearing a substituted phenoxy or hydroxybenzoylglutamate group on position 2, a carboethoxy or carboxy group on position 3 and a trifluoromethyl group on position 6 or 7 of the heterocycle were prepared in order to evaluate the in vitro anticancer activity. Screening over 21 compounds selected at the National Cancer Institute (Bethesda, MD) showed that only few derivatives exhibited a moderate growth inhibition activity on various tumor panel cell lines at 10(-4) molar concentration. The acid derivatives showed no growth inhibition activity. The results obtained in this series seem to indicate that in general carboxy or carboethoxy groups close to O-link with phenyl or benzoyl glutamates on position 2 are detrimental for anticancer activity.
Publication Date: 1998
Publication Name: Il Farmaco
Research Interests:
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Publication Date: 2012
Publication Name: Journal of Medicinal Chemistry
Research Interests:
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Synthesis and antiviral activity of new phenylimidazopyridines and N-benzylidenequinolinamines derived by molecular simplification of phenylimidazo[4,5-g]quinolinesmore
by Paola Corona and Giuseppe Paglietti
Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the... more
Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3H-imidazo[4,5-g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and N-benzylidenequinolinamines respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against representatives of two DNA virus families as wells as against representatives of RNA virus families containing single-stranded, either positive-sense (ssRNA(+)) or negative-sense (ssRNA(-)), and double-stranded genomes (dsRNA). Some imidazo[4,5-b]pyridines emerged as new derivatives endowed with antiviral activity against Vaccinia Virus (VV) at concentrations ranging from 2 to 16 μM. In particular, compound 2b demonstrate to be about 10 times more potent than Cidofovir, used as reference drug. Similarly, the imidazo[4,5-c]pyridines and N-benzylidenequinolinamines derivatives resulted active against Bovine Viral Diarrhoea virus (BVDV), at concentrations ranging from 1.2 to 28 μM. Above all compounds 1, 3a and 3f showed an EC50 of the same order of magnitude of the reference drug, the 2'-C-methyl-guanosine. Moreover, several N-benzylidenequinolinamines showed an interesting activity against Respiratory Syncytial Virus (RSV) at concentrations between 12 and 26 μM.
Publication Date: 2014
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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Publication Date: 2008
Publication Name: Medicinal Chemistry
Research Interests: Medicinal Chemistry, Magnetic Resonance Spectroscopy, RNA viruses, HIV, Humans, and 11 moreAnimals, C2H2 zinc fingers, Regression Analysis, Medicinal, Cell Proliferation, Benzimidazoles, Quntitative Thin Layer Chromatography, Structure activity Relationship, Antineoplastic Agents, Flaviviridae, and Antiviral Agents
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by Paola Corona and Giuseppe Paglietti
A series of novel 5,7-diamino-3-phenyl-2-benzylamino, 2-phenoxy, and 2-thiophenyl substituted quinoxalines has been designed, synthesized and evaluated for their in vitro antitumor activity towards cell lines of nine different types of... more
A series of novel 5,7-diamino-3-phenyl-2-benzylamino, 2-phenoxy, and 2-thiophenyl substituted quinoxalines has been designed, synthesized and evaluated for their in vitro antitumor activity towards cell lines of nine different types of human cancers. Some of these compounds exhibited inhibitory effects on the growth of a wide range of cancer cell lines generally at 10(-6) M, in some cases at 10(-7) M and 10(-8) M concentrations. Within this series the benzylamino quinoxaline derivatives 1b-7b were the most active, whereas compound 2c showed the highest MG_MD value (-5.66).
Publication Date: 2009
Publication Name: European journal of medicinal chemistry
Research Interests: Organic Chemistry, Medicinal Chemistry, Magnetic Resonance Spectroscopy, Cell Division, Cell line, and 13 moreHumans, Drug Design, European, Amino Acids, Bioorganic and medicinal Chemistry, Cell Proliferation, Pyrazoles, Antitumor Activity, Structure activity Relationship, Antineoplastic Agents, Butyrolactone, Molecular Structure, and Quinazolines
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Quinoxaline chemistry. Part 13: 3-carboxy-2-benzylamino-substituted quinoxalines and N-[4-[(3-carboxyquinoxalin-2-yl) aminomethyl]benzoyl]-l-glutamates: synthesis and evaluation of in vitro anticancer activitymore
by Paola Corona and Giuseppe Paglietti
Among a new series of 28 3-carboxy or carbethoxy quinoxalines bearing a substituted benzylamino or N-[4-(aminomethyl)benzoyl]glutamate group on position 2 of the ring and various substituents at C-6, 7 positions, 21 were selected at the... more
Among a new series of 28 3-carboxy or carbethoxy quinoxalines bearing a substituted benzylamino or N-[4-(aminomethyl)benzoyl]glutamate group on position 2 of the ring and various substituents at C-6, 7 positions, 21 were selected at the National Cancer Institute for evaluation of their in vitro anticancer activity. The results obtained seem to confirm that the carboxy or carbethoxy group on position 3 is not helpful, with a few exceptions, for the anticancer activity.
Publication Date: 2000
Research Interests:
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Publication Date: 1995
Publication Name: ChemInform
Research Interests:
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Quinoxaline Chemistry. Part 16. 4-Substituted Anilino and 4-Substituted Phenoxymethyl Pyrrolo[1,2-a]quinoxalines and N-[4-(Pyrrolo[1,2-a]quinoxalin-4-yl)amino and Hydroxymethyl]benzoyl Glutamates. Synthesis and Evaluation of in vitro Biological Activitymore
by Paola Corona and Giuseppe Paglietti
Twenty eight pyrrolo[1,2-a]quinoxalines bearing at position 4 various substituents related to the moieties present in classical and non classical antifolic agents were prepared and evaluated in vitro for antiproliferative activity. In an... more
Twenty eight pyrrolo[1,2-a]quinoxalines bearing at position 4 various substituents related to the moieties present in classical and non classical antifolic agents were prepared and evaluated in vitro for antiproliferative activity. In an in vitro screening performed at NCI, several compounds emerged as potent antiproliferative agents at concentrations ranging between 10 and 100 microM. Interestingly, some of these compounds proved active also against bovine and murine DHFR (Farmaco 53 (1998) 480). More recently, a compound of classical antifolate type has been reported to be a potent inhibitor of hDHFR in vitro (Farmaco 58 (2003) 51). We then synthesized new derivatives that, in our hands, were endowed with in vitro antiproliferative activities as low as 3.4 microM against a panel of cell lines derived from hematological and solid tumours. In addition, a complete screening of cytotoxicity, antiretroviral HIV-1 and antimicrobial activity has been carried out.
Publication Date: 2004
Publication Name: ChemInform
Research Interests:
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ChemInform Abstract: Quinoxaline Chemistry. Part 10. Quinoxaline 10-Oxa-analogues of Trimetrexate (TMQ) and of 5,8-Dideazafolic Acid. Synthesis and Evaluation of in vitro Anticancer Activitymore
by Paola Corona and Giuseppe Paglietti
Publication Date: 1998
Publication Name: ChemInform
Research Interests:
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Synthesis and antiviral activity of new phenylimidazopyridines and N-benzylidenequinolinamines derived by molecular simplification of phenylimidazo[4,5-g]quinolinesmore
by Paolo La Colla and Giuseppe Paglietti
Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the... more
Continuing our program of research concerning the antiviral activity of a wide series of new angular and linear azolo bicyclic and tricyclic derivatives, now we have simplified and modified the 4-chloro-2-(4-nitrophenyl)-3H-imidazo[4,5-g]quinoline 1, which previously resulted the most active derivative, through either the elimination of the central ring or the opening of the imidazole ring, obtaining various imidazopyridines and N-benzylidenequinolinamines respectively. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against representatives of two DNA virus families as wells as against representatives of RNA virus families containing single-stranded, either positive-sense (ssRNA(+)) or negative-sense (ssRNA(-)), and double-stranded genomes (dsRNA). Some imidazo[4,5-b]pyridines emerged as new derivatives endowed with antiviral activity against Vaccinia Virus (VV) at concentrations ranging from 2 to 16 μM. In particular, compound 2b demonstrate to be about 10 times more potent than Cidofovir, used as reference drug. Similarly, the imidazo[4,5-c]pyridines and N-benzylidenequinolinamines derivatives resulted active against Bovine Viral Diarrhoea virus (BVDV), at concentrations ranging from 1.2 to 28 μM. Above all compounds 1, 3a and 3f showed an EC50 of the same order of magnitude of the reference drug, the 2'-C-methyl-guanosine. Moreover, several N-benzylidenequinolinamines showed an interesting activity against Respiratory Syncytial Virus (RSV) at concentrations between 12 and 26 μM.
Publication Date: 2014
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select... more
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Publication Date: 2008
Publication Name: ChemInform
Research Interests:
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Quinoxaline chemistry Part 10. Quinoxaline 10-oxa-analogues of trimetrexate (TMQ ) and of 5,8-dideazafolic acid. Synthesis and evaluation of in vitro anticancer activitymore
by Paola Corona and Giuseppe Paglietti
Among twenty-eight novel compounds (twenty-two 2,3-disubstituted-6-[(substituted-phenoxy)methyl-quinoxalines and six 4-[(2,3-disubstituted-quinoxalin-6-yl methoxylbenzoylglutamates) only thirteen were selected at NO for evaluation of... more
Among twenty-eight novel compounds (twenty-two 2,3-disubstituted-6-[(substituted-phenoxy)methyl-quinoxalines and six 4-[(2,3-disubstituted-quinoxalin-6-yl methoxylbenzoylglutamates) only thirteen were selected at NO for evaluation of their in vitro anticancer activity. The results have shown that compounds 31,c,b,e and 4b were endowed with significantly high values of percent tumor growth inhibition on several tumor cell lines at 10−4 M, while compound 3t was characterized by a high selectivity, being still strongly inhibiting on three cell lines at 10−5 M. Comparison of the presently observed activity with that of the previously described aza-analogues confirms that the effected isosteric substitution is highly valuable in some cases.
Publication Date: 1998
Publication Name: Farmaco
Research Interests:
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Quinoxaline derivatives have received much attention in recent years owing to their both biological properties and pharmaceutical applications. In this review we focus the attention on quinoxalin-2(3)-ones and quinoxalin-2,3-diones. These... more
Quinoxaline derivatives have received much attention in recent years owing to their both biological properties and pharmaceutical applications. In this review we focus the attention on quinoxalin-2(3)-ones and quinoxalin-2,3-diones. These derivatives are particularly interesting since some of them showed antimicrobial (against several bacteria, viruses, fungi, etc), or anticancer activities. Furthermore, others are reported to be potent no-NMDA glutamate receptor antagonists, endowed with anxiolytic, deconditioning, analgesic, antispastic, antiallergic, antithrombotic activities. In this article we also report SAR studies and the most important methods of synthesis of the quinoxalin-2(3)-(di)ones.
Publication Date: 2006
Publication Name: Mini-Reviews in Medicinal Chemistry
Research Interests:
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by Paola Corona and Giuseppe Paglietti
Publication Date: 2009
Publication Name: Medicinal Chemistry
Research Interests: Medicinal Chemistry, Magnetic Resonance Spectroscopy, RNA viruses, HIV, Humans, and 11 moreAnimals, C2H2 zinc fingers, Regression Analysis, Medicinal, Cell Proliferation, Benzimidazoles, Quntitative Thin Layer Chromatography, Structure activity Relationship, Antineoplastic Agents, Flaviviridae, and Antiviral Agents
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A series N,N'-bis[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkyldicarboxamides (3a-f and 5a-j) were prepared starting from their already known (1a-d) and (4a-c) or new (4d) amine parents. Because of the antiviral activity of several... more
A series N,N'-bis[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkyldicarboxamides (3a-f and 5a-j) were prepared starting from their already known (1a-d) and (4a-c) or new (4d) amine parents. Because of the antiviral activity of several N-[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkylcarboxamides previously reported, title compounds were evaluated in vitro for cytotoxicity and antiviral activity against viruses representative of Picornaviridae, [i.e. Enterovirus Coxsackie B2 (CVB-2) and Polio (Sb-1)] and of two of the three genera of the Flaviviridae [Bovine Viral Diarrhea Virus (BVDV) and Yellow Fever Virus (YFV)]. Furthermore, because of the in silico activity against the RNA-dependent RNA-helicase of Polio 1 previously reported, title compounds were evaluated against the 3D model of the Sb-1 helicase and against the 2D model of the CVB-2 helicase. As a reference we used the antiviral and in silico activities of an imidazo counterpart of the title compounds, N,N'-bis[4-(2-benzimidazolyl)phenyl]alkyldicarboxamides (III) that other authors reported to be able to inhibit the corresponding enzyme of Hepatitis C Virus (HCV). In cell-based antiviral assays, N,N'-bis[4-(1H-benzotriazol-1-yl)phenyl]alkyldicarboxamides (3a-f) resulted completely inactive whereas the bis-5,6-dimethyl-benzotriazol-2-yl derivatives (5d-f) exhibited good activity against the Enteroviruses, (EC(50)s ranged between 7 and 11 microM against CVB-2 and 19-52 against Sb-1). Interestingly, bis-5,6-dichloro-benzotriazol-2-yl derivatives (5h-j) showed very selective activity against CVB-2 (EC(50)s = 4-11 microM) whereas they resulted completely inactive against all the other viruses screened. In general, all title compounds showed a good cytotoxicity profile in MT-4 cells. Molecular modeling investigations showed that active compounds may interact with the binding site of the Sb-1 helicase and that their free binding energy values are in agreement with their EC(50)s values.
Publication Date: 2007
Publication Name: Medicinal Chemistry
Research Interests:
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Publication Date: 1999
Publication Name: Heterocycles
Research Interests:
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Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a... more
Pteridine reductase (PTR1) is essential for salvage of pterins by parasitic trypanosomatids and is a target for the development of improved therapies. To identify inhibitors of Leishmania major and Trypanosoma cruzi PTR1, we combined a rapid-screening strategy using a folate-based library with structure-based design. Assays were carried out against folate-dependent enzymes including PTR1, dihydrofolate reductase (DHFR), and thymidylate synthase. Affinity profiling determined selectivity and specificity of a series of quinoxaline and 2,4-diaminopteridine derivatives, and nine compounds showed greater activity against parasite enzymes compared with human enzymes. Compound 6a displayed a K(i) of 100 nM toward LmPTR1, and the crystal structure of the LmPTR1:NADPH:6a ternary complex revealed a substrate-like binding mode distinct from that previously observed for similar compounds. A second round of design, synthesis, and assay produced a compound (6b) with a significantly improved K(i) ...
Publisher: ncbi.nlm.nih.gov
Publication Date: Jan 5, 2008
Publication Name: Proceedings of the National Academy of Sciences of the United States of America
Research Interests: Drug Discovery, Enzyme Inhibitors, Drug development, Folic acid, Multidisciplinary, and 12 moreMacromolecular X-Ray Crystallography, Crystal structure, Animals, Drug Resistance, Oxidoreductases, Drug Design, Enzyme, Trypanosoma Cruzi, Trypanocidal Agents, Protozoan Proteins, Leishmania Major, and Dihydrofolate Reductase
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Publication Date: 2003
Publication Name: Journal of Chemical Research (Miniprint)
Research Interests:
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Publication Date: 2004
Publication Name: Il Farmaco
Research Interests:
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Publication Date: 2003
Publication Name: HETEROCYCLES
Research Interests:
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Publication Date: 2000
Publication Name: HETEROCYCLES
Research Interests:
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Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one... more
Based on our previous results on the ascertained potent growth inhibition effect against a panel of 60 human tumors cell lines at National Cancer Institute of Bethesda (NCI), we have synthesized a novel series of thirty-one 2-[N-methyl(R-phenyl)-aminomethyl]-3-phenyl-7-trifluoromethylquinoxalines (1-31). The lead compound 1 was previously reported to be endowed with significant inhibition against hDHFR enzyme, with a Ki of 0.2 μM. Docking studies were performed on compound 1 and here reported to predict its binding conformation to human dihydrofolate reductase (hDHFR). All compounds (1-31) were assayed versus hDHFR and human thymidylate synthase (hTS). From the screening emerged that all compounds inhibited hDHFR with Ki values included between 0.2 and 11 μM, while only a few (6, 21, 24, 27, 29) showed great activity and selectivity towards hTS. Evaluation of the anticancer activity was performed by NCI, first against the three cell line panel, and only the most active compounds (17, 21, 24, 26, 27) were evaluated on a panel of 60 human tumor cell lines. Compound 21 was the most active against all cell lines with log GI50 equal to -5.49 and log LC50 equal to -4.19 and maintained significant percent of growth inhibition on seven cancer cell lines at the concentration of 1 μM. Compound 17 was the second most active and moreover showed interesting selectivity against some cell lines (Lung cancer: A549/ATCC, Melanoma: UACC-257, Ovarian Cancer: ovcar-8 and Renal cancer: RXF 393) at all concentration examined (100-0.01 μM).
Publication Date: 2014
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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Publication Date: 2004
Publication Name: European Journal of Medicinal Chemistry
Research Interests: Organic Chemistry, Mycobacterium tuberculosis, Escherichia coli, Gram Positive, Animals, and 13 moreStaphylococcus aureus, Trichomonas vaginalis, Candida albicans, Pseudomonas aeruginosa, European, Antibacterial activity, Gram-negative bacteria, Anti-Bacterial Agents, Antifungal Agents, Microbial Sensitivity Tests, Pseudomonas Aeruginosa, Molecular Structure, and Klebsiella pneumoniae
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Publication Date: 2002
Publication Name: European Journal of Medicinal Chemistry
Research Interests:
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Publication Date: 2007
Publication Name: Bioorganic & Medicinal Chemistry Letters
Research Interests:
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Publication Date: 2010
Publication Name: Bioorganic & Medicinal Chemistry
Research Interests: Chemistry, Organic Chemistry, DNA viruses, RNA viruses, Cercopithecus aethiops, and 20 moreCell line, Humans, Animals, Cattle, Human Respiratory Syncytial Viruses, Flavivirus, Microbial Sensitivity Tests, Bioorganic and medicinal Chemistry, Cell Proliferation, Benzimidazoles, Antiviral Activity, Structure activity Relationship, Structural Similarity Index, Cell Survival, Vero cells, Antiviral Agents, Molecular Structure, Poliovirus, Enterovirus, and Pestivirus
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Publisher: ingentaconnect.com
Publication Date: 2009
Publication Name: Letters in Drug …
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Publication Date: 2001
Publication Name: Archiv der Pharmazie
Research Interests:
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4-Substituted anilino imidazo[1,2-a] and triazolo[4,3-a]quinoxalines. Synthesis and evaluation of in vitro biological activitymore
by Paolo La Colla and Giuseppe Paglietti