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.
N1 - Funding Information:
We thank William R. Jacobs, Jr. (Albert Einstein College of Medicine), for the kind donation of strain mc26206 and Jeffrey S. Cox (UC Berkeley) for the gracious donation of the mLux plasmid. We thank Xin Wang (Rutgers University) and Sean Ekins (Collaborations Pharmaceuticals) for critical comments during the course of this project. This work was supported by NIH grant U19AI109713.
Publisher Copyright:
Copyright © 2018 American Society for Microbiology. All Rights Reserved.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/3
Y1 - 2018/3
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
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U2 - 10.1128/AAC.02063-17
DO - 10.1128/AAC.02063-17
M3 - Article
C2 - 29311070
AN - SCOPUS:85042412222
VL - 62
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 3
M1 - e02063-1
ER -