Abstract
Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
| Original language | English (US) |
|---|---|
| Article number | e02063-1 |
| Journal | Antimicrobial agents and chemotherapy |
| Volume | 62 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2018 |
| Externally published | Yes |
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Keywords
- Antitubercular
- Mycobacterium tuberculosis
- Pharmacokinetics
- Pyrimidine
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
- Infectious Diseases
Cite this
Novel pyrimidines as antitubercular agents. / Inoyama, Daigo; Paget, Steven D.; Russo, Riccardo; Kandasamy, Srinivasan; Kumar, Pradeep; Singleton, Eric; Occi, James; Tuckman, Margareta; Zimmerman, Matthew D.; Ho, Hsin Pin; Perryman, Alexander L.; Dartois, Véronique; Connell, Nancy; Freundlicha, Joel S.
In: Antimicrobial agents and chemotherapy, Vol. 62, No. 3, e02063-1, 01.03.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel pyrimidines as antitubercular agents
AU - Inoyama, Daigo
AU - Paget, Steven D.
AU - Russo, Riccardo
AU - Kandasamy, Srinivasan
AU - Kumar, Pradeep
AU - Singleton, Eric
AU - Occi, James
AU - Tuckman, Margareta
AU - Zimmerman, Matthew D.
AU - Ho, Hsin Pin
AU - Perryman, Alexander L.
AU - Dartois, Véronique
AU - Connell, Nancy
AU - Freundlicha, Joel S.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
AB - Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
KW - Antitubercular
KW - Mycobacterium tuberculosis
KW - Pharmacokinetics
KW - Pyrimidine
UR - http://www.scopus.com/inward/record.url?scp=85042412222&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042412222&partnerID=8YFLogxK
U2 - 10.1128/AAC.02063-17
DO - 10.1128/AAC.02063-17
M3 - Article
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 3
M1 - e02063-1
ER -