Synthetic Calanolides with
Bactericidal Activity against
Replicating and Nonreplicating Mycobacterium tuberculosis
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Abstract
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