Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis

The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. Our focused set of compounds was synthesized and screened against three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and the clinical isolate Mycobacterium tuberculosis N0145 with and without the cytochrome bcc:aa3 inhibitor Q203 in an ATP depletion assay. Two compounds, 12a and 19a, were more active against all three strains than the naturally derived cyt-bd inhibitor aurachin D.

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IN VITRO ACTIVITY OF CEPHALOSPORINS AGAINST MYCOBACTERIUM TUBERCULOSIS H37Rv: STRUCTURE-ACTIVITY RELATIONSHIPS

The Journal of Antibiotics ◽

10.7164/antibiotics.26.737 ◽

1973 ◽

Vol 26 (12) ◽

pp. 737-744 ◽

Cited By ~ 6

Author(s):

M. MISIEK ◽

A. J. MOSES ◽

T. A. PURSIANO ◽

F. LEITNER ◽

K. E. PRICE

Keyword(s):

Mycobacterium Tuberculosis ◽

Tuberculosis H37rv ◽

Vitro Activity ◽

In Vitro Activity ◽

Structure Activity Relationships ◽

Mycobacterium Tuberculosis H37rv ◽

Structure Activity

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Synthesis and structure-activity relationships for tetrahydroisoquinoline-based inhibitors of Mycobacterium tuberculosis

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2020.115784 ◽

2020 ◽

Vol 28 (22) ◽

pp. 115784

Author(s):

Guo-Liang Lu ◽

Amy S.T. Tong ◽

Daniel Conole ◽

Hamish S. Sutherland ◽

Peter J. Choi ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Structure Activity Relationships ◽

Structure Activity

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Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-oxidase

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2015.11.017 ◽

2015 ◽

Vol 23 (24) ◽

pp. 7694-7710 ◽

Cited By ~ 21

Author(s):

Sudhir Landge ◽

Amrita B. Mullick ◽

Kavitha Nagalapur ◽

João Neres ◽

Venkita Subbulakshmi ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Binding Studies ◽

Structure Activity Relationships ◽

Structure Activity ◽

Antimycobacterial Agents

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Synergistic Lethality of a Binary Inhibitor ofMycobacterium tuberculosisKasA

mBio ◽

10.1128/mbio.02101-17 ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 14

Author(s):

Pradeep Kumar ◽

Glenn C. Capodagli ◽

Divya Awasthi ◽

Riju Shrestha ◽

Karishma Maharaja ◽

...

Keyword(s):

Crystal Structure ◽

Cell Wall ◽

Mycobacterium Tuberculosis ◽

Substrate Binding ◽

Content Type ◽

X Ray ◽

Structure Activity Relationships ◽

Structure Activity ◽

Transcriptional Pattern

ABSTRACTWe report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) inMycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented thein vitroactivity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model ofM. tuberculosisinfection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB).IMPORTANCECell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors ofMycobacterium tuberculosisKasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.

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