Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis

Sandeep Thanna; Susan E. Knudson; Anna Grzegorzewicz; Sunayana Kapil; Christopher M. Goins; Donald R. Ronning; Mary Jackson; Richard A. Slayden; Steven J. Sucheck

doi:10.1039/c6ob00821f

Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis

Sandeep Thanna, Susan E. Knudson, Anna Grzegorzewicz, Sunayana Kapil, Christopher M. Goins, Donald R. Ronning, Mary Jackson, Richard A. Slayden, Steven J. Sucheck

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37R_V (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.

Original language	English (US)
Pages (from-to)	6119-6133
Number of pages	15
Journal	Organic and Biomolecular Chemistry
Volume	14
Issue number	25
DOIs	https://doi.org/10.1039/c6ob00821f
State	Published - 2016
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Physical and Theoretical Chemistry
Organic Chemistry

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title = "Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis",

abstract = "Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.",

author = "Sandeep Thanna and Knudson, {Susan E.} and Anna Grzegorzewicz and Sunayana Kapil and Goins, {Christopher M.} and Ronning, {Donald R.} and Mary Jackson and Slayden, {Richard A.} and Sucheck, {Steven J.}",

note = "Publisher Copyright: {\textcopyright} The Royal Society of Chemistry 2016.",

year = "2016",

doi = "10.1039/c6ob00821f",

language = "English (US)",

volume = "14",

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TY - JOUR

T1 - Synthesis and evaluation of new 2-aminothiophenes against

T2 - Mycobacterium tuberculosis

AU - Thanna, Sandeep

AU - Knudson, Susan E.

AU - Grzegorzewicz, Anna

AU - Kapil, Sunayana

AU - Goins, Christopher M.

AU - Ronning, Donald R.

AU - Jackson, Mary

AU - Slayden, Richard A.

AU - Sucheck, Steven J.

PY - 2016

Y1 - 2016

N2 - Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.

AB - Tuberculosis (TB) and its drug resistant forms kills more people than any other infectious disease. This fact emphasizes the need to identify new drugs to treat TB. 2-Aminothiophenes (2AT) have been reported to inhibit Pks13, a validated anti-TB drug target. We synthesized a library of 42 2AT compounds. Among these, compound 33 showed remarkable potency against Mycobacterium tuberculosis (Mtb) H37RV (MIC = 0.23 μM) and showed an impressive potency (MIC = 0.20-0.44 μM) against Mtb strains resistant to isoniazid, rifampicin and fluoroquinolones. The site of action for the compound 33 is presumed to be Pks13 or an earlier enzyme in the mycolic acid biosynthetic pathway. This inference is based on structural similarity of the compound 33 with known Pks13 inhibitors, which is corroborated by mycolic acid biosynthesis studies showing that the compound strongly inhibits the biosynthesis of all forms of mycolic acid in Mtb. In summary, these studies suggest 33 represents a promising anti-TB lead that exhibits activity well below toxicity to human monocytic cells.

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Synthesis and evaluation of new 2-aminothiophenes against: Mycobacterium tuberculosis

Abstract

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