Abstract
8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 348-351 |
| Number of pages | 4 |
| Journal | ACS Medicinal Chemistry Letters |
| Volume | 10 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 14 2019 |
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Keywords
- antitubercular
- benzothiazinone
- spirocyclic
- tuberculosis
PubMed: MeSH publication types
- Journal Article
Cite this
Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties. / Zhang, Gang; Howe, Michael; Aldrich, Courtney.
In: ACS Medicinal Chemistry Letters, Vol. 10, No. 3, 14.03.2019, p. 348-351.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties
AU - Zhang, Gang
AU - Howe, Michael
AU - Aldrich, Courtney
PY - 2019/3/14
Y1 - 2019/3/14
N2 - 8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters.
AB - 8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters.
KW - antitubercular
KW - benzothiazinone
KW - spirocyclic
KW - tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85062881681&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062881681&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.8b00634
DO - 10.1021/acsmedchemlett.8b00634
M3 - Article
VL - 10
SP - 348
EP - 351
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 3
ER -