The Experts below are selected from a list of 1107 Experts worldwide ranked by ideXlab platform
William R Bishai - One of the best experts on this subject based on the ideXlab platform.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II.
Journal of Medicinal Chemistry, 2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis ( Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure-activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II
2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis (Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure–activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors Against Mycobacterium Tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of th...
-
identification of novel Coumestan derivatives as polyketide synthase 13 inhibitors against mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents
François Noël - One of the best experts on this subject based on the ideXlab platform.
-
insights into the mechanism of na k atpase inhibition by 2 methoxy 3 8 9 trihydroxy Coumestan
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Elisa S.c. Pôças, Alcides J. M. Da Silva, Paulo R R Costa, Natália Araújo Touza, Paulo Henrique Cotrim Pimenta, Fernanda Leitão, Chaquip D. Neto, François NoëlAbstract:The molecular mechanisms involved in Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy Coumestan were investigated. We show that this compound decreases the free sulfydryl groups present in the enzyme and that its inhibitory effect is prevented by dithiothreitol and other two sulfydryl containing reagents. We propose a redox cycle culminating with the irreversible oxidation of sulfydryl groups essential for the catalytic activity of this enzyme and of two other related P-type ATPases.
-
Identification and characterization of Coumestans as novel HCV NS5B polymerase inhibitors.
Nucleic Acids Research, 2008Co-Authors: Neerja Kaushik-basu, Alcides J. M. Da Silva, Paulo R R Costa, Alain Bopda-waffo, Tanaji T. Talele, Amartya Basu, Stefan G. Sarafianos, François NoëlAbstract:The hepatitis C virus (HCV) NS5B is essential for viral RNA replication and is therefore a prime target for development of HCV replication inhibitors. Here, we report the identification of a new class of HCV NS5B inhibitors belonging to the Coumestan family of phytoestrogens. Based on the in vitro NS5B RNA-dependent RNA polymerase (RdRp) inhibition in the low micromolar range by wedelolactone, a naturally occurring Coumestan, we evaluated the anti-NS5B activity of four synthetic Coumestan analogues bearing different patterns of substitutions in their A and D rings, and observed a good structure-activity correlation. Kinetic characterization of Coumestans revealed a noncompetitive mode of inhibition with respect to nucleoside triphosphate (rNTP) substrate and a mixed mode of inhibition towards the nucleic acid template, with a major competitive component. The modified order of addition experiments with Coumestans and nucleic acid substrates affected the potencies of the Coumestan inhibitors. Coumestan interference at the step of NS5B-RNA binary complex formation was confirmed by cross-linking experiments. Molecular docking of Coumestans within the allosteric site of NS5B yielded significant correlation between their calculated binding energies and IC(50) values. Coumestans thus add to the diversifying pool of anti-NS5B agents and provide a novel scaffold for structural refinement and development of potent NS5B inhibitors.
-
Insights into the mechanism of Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy Coumestan.
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Elisa S.c. Pôças, Alcides J. M. Da Silva, Paulo R R Costa, Natália Araújo Touza, Paulo Henrique Cotrim Pimenta, Fernanda Leitão, Chaquip D. Neto, François NoëlAbstract:The molecular mechanisms involved in Na+,K+-ATPase inhibition by 2-methoxy-3,8,9-trihydroxy Coumestan were investigated. We show that this compound decreases the free sulfydryl groups present in the enzyme and that its inhibitory effect is prevented by dithiothreitol and other two sulfydryl containing reagents. We propose a redox cycle culminating with the irreversible oxidation of sulfydryl groups essential for the catalytic activity of this enzyme and of two other related P-type ATPases.
-
2 methoxy 3 8 9 trihydroxy Coumestan a new synthetic inhibitor of na k atpase with an original mechanism of action
Biochemical Pharmacology, 2003Co-Authors: Elisa S.c. Pôças, Alcides J. M. Da Silva, Paulo R R Costa, François NoëlAbstract:The aim of the present work was to analyse the interaction between Na(+),K(+)-ATPase and one of our recent synthesized Coumestans, namely the original molecule 2-methoxy-3,8,9-trihydroxy Coumestan (PCALC36). Rat brain (mainly alpha 2 and alpha 3 Na(+),K(+)-ATPase isoforms) and kidney (alpha 1 isoform) fractions enriched with Na(+),K(+)-ATPase were utilized to compare the inhibition promoted by PCALC36 with that of classical inhibitors like ouabain and vanadate. Analysis of inhibition curves revealed that unlike ouabain, which was about a thousand times more potent to inhibit brain isoforms than kidney isoform, PCALC36 had a similar affinity for brain (IC(50)=4.33+/-0.90 microM) and kidney (IC(50)=11.04+/-0.86 microM) isoforms. The inhibitory effect of PCALC36 was not antagonized by 1-10 mM K(+), as observed with ouabain. Whereas vanadate was more potent in ionic conditions promoting the E2 conformation of the enzyme, the inhibitory effect of PCALC36 was equal in ionic conditions favouring either the E1 or E2 conformations. Equilibrium binding assays with [3H]ouabain revealed that the addition of 2-10 microM PCALC36 did not change the K(d) of ouabain but decreased its maximal binding (B(max)) in a concentration-dependent manner (from 76.6 to 44.0 pmol/mg protein). This inhibitory effect of PCALC36 was not reverted after an extensive washing procedure indicating that it forms a very stable complex with Na(+),K(+)-ATPase. We conclude that PCALC36, a new molecule with a non-steroidal skeleton, inhibits the Na(+),K(+)-ATPase by a mechanism of action different from the cardiac glycosides and could thus serve as a structural paradigm to develop new inotropic drugs.
-
2-Methoxy-3,8,9-trihydroxy Coumestan: a new synthetic inhibitor of Na+,K+-ATPase with an original mechanism of action
Biochemical Pharmacology, 2003Co-Authors: Elisa S.c. Pôças, Alcides J. M. Da Silva, Paulo R R Costa, François NoëlAbstract:The aim of the present work was to analyse the interaction between Na(+),K(+)-ATPase and one of our recent synthesized Coumestans, namely the original molecule 2-methoxy-3,8,9-trihydroxy Coumestan (PCALC36). Rat brain (mainly alpha 2 and alpha 3 Na(+),K(+)-ATPase isoforms) and kidney (alpha 1 isoform) fractions enriched with Na(+),K(+)-ATPase were utilized to compare the inhibition promoted by PCALC36 with that of classical inhibitors like ouabain and vanadate. Analysis of inhibition curves revealed that unlike ouabain, which was about a thousand times more potent to inhibit brain isoforms than kidney isoform, PCALC36 had a similar affinity for brain (IC(50)=4.33+/-0.90 microM) and kidney (IC(50)=11.04+/-0.86 microM) isoforms. The inhibitory effect of PCALC36 was not antagonized by 1-10 mM K(+), as observed with ouabain. Whereas vanadate was more potent in ionic conditions promoting the E2 conformation of the enzyme, the inhibitory effect of PCALC36 was equal in ionic conditions favouring either the E1 or E2 conformations. Equilibrium binding assays with [3H]ouabain revealed that the addition of 2-10 microM PCALC36 did not change the K(d) of ouabain but decreased its maximal binding (B(max)) in a concentration-dependent manner (from 76.6 to 44.0 pmol/mg protein). This inhibitory effect of PCALC36 was not reverted after an extensive washing procedure indicating that it forms a very stable complex with Na(+),K(+)-ATPase. We conclude that PCALC36, a new molecule with a non-steroidal skeleton, inhibits the Na(+),K(+)-ATPase by a mechanism of action different from the cardiac glycosides and could thus serve as a structural paradigm to develop new inotropic drugs.
Wei Zhang - One of the best experts on this subject based on the ideXlab platform.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II.
Journal of Medicinal Chemistry, 2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis ( Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure-activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II
2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis (Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure–activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors Against Mycobacterium Tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of th...
-
identification of novel Coumestan derivatives as polyketide synthase 13 inhibitors against mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents
Jie Tang - One of the best experts on this subject based on the ideXlab platform.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II.
Journal of Medicinal Chemistry, 2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis ( Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure-activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II
2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis (Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure–activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors Against Mycobacterium Tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of th...
-
identification of novel Coumestan derivatives as polyketide synthase 13 inhibitors against mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents
Fan Yang - One of the best experts on this subject based on the ideXlab platform.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II.
Journal of Medicinal Chemistry, 2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis ( Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure-activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II
2019Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Ling-ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, William R BishaiAbstract:Our group recently reported the identification of novel Coumestan derivatives as Mycobacterium tuberculosis (Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated Coumestan-resistant Mtb colonies. Herein, we report a further structure–activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent Coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of Coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the Coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the Coumestan derivatives
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors Against Mycobacterium Tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of th...
-
identification of novel Coumestan derivatives as polyketide synthase 13 inhibitors against mycobacterium tuberculosis
Journal of Medicinal Chemistry, 2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.
-
Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
2018Co-Authors: Wei Zhang, Fan Yang, Jie Tang, Shichun Lun, Hendra Gunosewoyo, Shu Huan Wang, Xing Wu Jiang, Abigail L. Manson, Ashlee M. Earl, William R BishaiAbstract:Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure–activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form Coumestans that are shown to be active in SIT. Whole genome deep sequencing of the Coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents
