Synthetic calanolides with bactericidal activity against replicating and nonreplicating Mycobacterium tuberculosis.
It is urgent to introduce new drugs for tuberculosis to shorten the prolonged course of treatment and control drug-resistant Mycobacterium tuberculosis (Mtb). One strategy toward this goal is to develop antibiotics that eradicate both replicating (R) and nonreplicating (NR) Mtb. Naturally occurring (+)-calanolide A was active against R-Mtb. The present report details the design, synthesis, antimycobacterial activities, and structure-activity relationships of synthetic calanolides. We identified potent dual-active nitro-containing calanolides with minimal in vitro toxicity that were cidal to axenic Mtb and Mtb in human macrophages, while sparing Gram-positive and -negative bacteria and yeast. Two of the nitrobenzofuran-containing lead compounds were found to be genotoxic to mammalian cells. Although genotoxicity precluded clinical progression, the profound, selective mycobactericidal activity of these calanolides will be useful in identifying pathways for killing both R- and NR-Mtb, as well as in further structure-based design of more effective and drug-like antimycobacterial agents.
Tsinghua-Peking Center for Life Sciences and ‡Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University , Haidian Dist., Beijing 100084, P. R. China.
Purong
P
Zheng
Selin
S
Somersan-Karakaya
Shichao
S
Lu
Julia
J
Roberts
Maneesh
M
Pingle
Thulasi
T
Warrier
David
D
Little
Xiaoyong
X
Guo
Steven J
SJ
Brickner
Carl F
CF
Nathan
Ben
B
Gold
Gang
G
Liu
D000995:Antitubercular Agents / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D039681:Pyranocoumarins / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D039681:Pyranocoumarins