Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 9, Pages 6541-6554Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01845
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Funding
- National Natural Science Foundation of China [81725020, 81973175, 82003591]
- Innovation Program of Shanghai Municipal Education Commission [2019-0107-00-07-E00073]
- Science and Technology Commission of Shanghai Municipality [20S11900400]
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This study successfully improved the antifungal activity of novel sertraline derivatives, with compound D16 showing promising potential as a treatment for cryptococcal meningitis.
Treatment of life-threatening cryptococcal meningitis (CM) ishighly challenging due to the limited efficacy of the available antifungal drugs.Antidepressant sertraline (SER) has been proposed to be a potentialantifungal agent for CM. However, clinical studies indicated that SER failedto achieve the expected therapeutic effects. Herein, novel SER derivativeswere designed by scaffold hopping, and they showed improvedanticryptococcal activity bothin vitroandin vivo. In particular, compoundD16was identified as a promising anti-CM agent with a new antifungal modeof action. It acted by blocking the biosynthesis of ergosterol through theinhibition of Delta 5,6-desaturase. This study provides a new target and a drug-likecandidate for CM treatment
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