Synthetic calanolides with bactericidal activity against replicating and nonreplicating Mycobacterium tuberculosis
| Autor: | Maneesh Pingle, Purong Zheng, Gang Liu, Ben Gold, Shi-Chao Lu, David Little, Carl Nathan, Xiaoyong Guo, Steven J. Brickner, Thulasi Warrier, Selin Somersan-Karakaya, Julia Roberts |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Tuberculosis
biology medicine.drug_class Antibiotics Antitubercular Agents Microbial Sensitivity Tests Mycobacterium tuberculosis biology.organism_classification Antimycobacterial medicine.disease Virology Pyranocoumarins Microbiology Structure-Activity Relationship Drug Discovery Calanolides medicine Molecular Medicine Structure–activity relationship Axenic Bacteria |
| Zdroj: | Journal of medicinal chemistry. 57(9) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|