8 research outputs found
Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors
Developing drugs for brain infection by Naegleria
fowleri is an unmet medical need. We used a combination
of cheminformatics, target-, and phenotypic-based drug discovery methods
to identify inhibitors that target an essential N.
fowleri enzyme, sterol 14-demethylase (NfCYP51). A
total of 124 compounds preselected in silico were
tested against N. fowleri. Nine primary
hits with EC50 ≤ 10 μM were phenotypically
identified. Cocrystallization with NfCYP51 focused attention on one
primary hit, miconazole-like compound 2a. The S-enantiomer of 2a produced a 1.74 Ã… cocrystal
structure. A set of analogues was then synthesized and evaluated to
confirm the superiority of the S-configuration over
the R-configuration and the advantage of an ether
linkage over an ester linkage. The two compounds, S-8b and S-9b, had an improved
EC50 and KD compared to 2a. Importantly, both were readily taken up into the brain.
The brain-to-plasma distribution coefficient of S-9b was 1.02 ± 0.12, suggesting further evaluation
as a lead for primary amoebic meningoencephalitis
Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri-Specific CYP51 Inhibitors
Developing drugs for brain infection by Naegleria
fowleri is an unmet medical need. We used a combination
of cheminformatics, target-, and phenotypic-based drug discovery methods
to identify inhibitors that target an essential N.
fowleri enzyme, sterol 14-demethylase (NfCYP51). A
total of 124 compounds preselected in silico were
tested against N. fowleri. Nine primary
hits with EC50 ≤ 10 μM were phenotypically
identified. Cocrystallization with NfCYP51 focused attention on one
primary hit, miconazole-like compound 2a. The S-enantiomer of 2a produced a 1.74 Ã… cocrystal
structure. A set of analogues was then synthesized and evaluated to
confirm the superiority of the S-configuration over
the R-configuration and the advantage of an ether
linkage over an ester linkage. The two compounds, S-8b and S-9b, had an improved
EC50 and KD compared to 2a. Importantly, both were readily taken up into the brain.
The brain-to-plasma distribution coefficient of S-9b was 1.02 ± 0.12, suggesting further evaluation
as a lead for primary amoebic meningoencephalitis
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
Heparanase is the
sole mammalian enzyme capable of cleaving glycosaminoglycan
heparan sulfate side chains of heparan sulfate proteoglycans. Its
altered activity is intimately associated with tumor growth, angiogenesis,
and metastasis. Thus, its implication in cancer progression makes
it an attractive target in anticancer therapy. Herein, we describe
the design, synthesis, and biological evaluation of new benzazoles
as heparanase inhibitors. Most of the designed derivatives were active
at micromolar or submicromolar concentration, and the most promising
compounds are fluorinated and/or amino acids derivatives <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 0.16–0.82 μM. Molecular docking studies were performed
to rationalize their interaction with the enzyme catalytic site. Importantly,
invasion assay confirmed the antimetastatic potential of compounds <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
Heparanase is the
sole mammalian enzyme capable of cleaving glycosaminoglycan
heparan sulfate side chains of heparan sulfate proteoglycans. Its
altered activity is intimately associated with tumor growth, angiogenesis,
and metastasis. Thus, its implication in cancer progression makes
it an attractive target in anticancer therapy. Herein, we describe
the design, synthesis, and biological evaluation of new benzazoles
as heparanase inhibitors. Most of the designed derivatives were active
at micromolar or submicromolar concentration, and the most promising
compounds are fluorinated and/or amino acids derivatives <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 0.16–0.82 μM. Molecular docking studies were performed
to rationalize their interaction with the enzyme catalytic site. Importantly,
invasion assay confirmed the antimetastatic potential of compounds <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
Heparanase is the
sole mammalian enzyme capable of cleaving glycosaminoglycan
heparan sulfate side chains of heparan sulfate proteoglycans. Its
altered activity is intimately associated with tumor growth, angiogenesis,
and metastasis. Thus, its implication in cancer progression makes
it an attractive target in anticancer therapy. Herein, we describe
the design, synthesis, and biological evaluation of new benzazoles
as heparanase inhibitors. Most of the designed derivatives were active
at micromolar or submicromolar concentration, and the most promising
compounds are fluorinated and/or amino acids derivatives <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 0.16–0.82 μM. Molecular docking studies were performed
to rationalize their interaction with the enzyme catalytic site. Importantly,
invasion assay confirmed the antimetastatic potential of compounds <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
Heparanase is the
sole mammalian enzyme capable of cleaving glycosaminoglycan
heparan sulfate side chains of heparan sulfate proteoglycans. Its
altered activity is intimately associated with tumor growth, angiogenesis,
and metastasis. Thus, its implication in cancer progression makes
it an attractive target in anticancer therapy. Herein, we describe
the design, synthesis, and biological evaluation of new benzazoles
as heparanase inhibitors. Most of the designed derivatives were active
at micromolar or submicromolar concentration, and the most promising
compounds are fluorinated and/or amino acids derivatives <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 0.16–0.82 μM. Molecular docking studies were performed
to rationalize their interaction with the enzyme catalytic site. Importantly,
invasion assay confirmed the antimetastatic potential of compounds <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
Heparanase is the
sole mammalian enzyme capable of cleaving glycosaminoglycan
heparan sulfate side chains of heparan sulfate proteoglycans. Its
altered activity is intimately associated with tumor growth, angiogenesis,
and metastasis. Thus, its implication in cancer progression makes
it an attractive target in anticancer therapy. Herein, we describe
the design, synthesis, and biological evaluation of new benzazoles
as heparanase inhibitors. Most of the designed derivatives were active
at micromolar or submicromolar concentration, and the most promising
compounds are fluorinated and/or amino acids derivatives <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 0.16–0.82 μM. Molecular docking studies were performed
to rationalize their interaction with the enzyme catalytic site. Importantly,
invasion assay confirmed the antimetastatic potential of compounds <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells
Novel Benzazole Derivatives Endowed with Potent Antiheparanase Activity
Heparanase is the
sole mammalian enzyme capable of cleaving glycosaminoglycan
heparan sulfate side chains of heparan sulfate proteoglycans. Its
altered activity is intimately associated with tumor growth, angiogenesis,
and metastasis. Thus, its implication in cancer progression makes
it an attractive target in anticancer therapy. Herein, we describe
the design, synthesis, and biological evaluation of new benzazoles
as heparanase inhibitors. Most of the designed derivatives were active
at micromolar or submicromolar concentration, and the most promising
compounds are fluorinated and/or amino acids derivatives <b>13a</b>, <b>14d</b>, and <b>15</b> that showed IC<sub>50</sub> 0.16–0.82 μM. Molecular docking studies were performed
to rationalize their interaction with the enzyme catalytic site. Importantly,
invasion assay confirmed the antimetastatic potential of compounds <b>14d</b> and <b>15</b>. Consistently with its ability to
inhibit heparanase, compound <b>15</b> proved to decrease expression
of genes encoding for proangiogenic factors such as MMP-9, VEGF, and
FGFs in tumor cells