Discovery of Novel Sertraline Derivatives as Potent Anti-Cryptococcus Agents. 2022

Wang Li, and Zhaolin Yun, and Changjin Ji, and Jie Tu, and Wanzhen Yang, and Jian Li, and Na Liu, and Chunquan Sheng
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.

Treatment of life-threatening cryptococcal meningitis (CM) is highly challenging due to the limited efficacy of the available antifungal drugs. Antidepressant sertraline (SER) has been proposed to be a potential antifungal agent for CM. However, clinical studies indicated that SER failed to achieve the expected therapeutic effects. Herein, novel SER derivatives were designed by scaffold hopping, and they showed improved anticryptococcal activity both in vitro and in vivo. In particular, compound D16 was identified as a promising anti-CM agent with a new antifungal mode of action. It acted by blocking the biosynthesis of ergosterol through the inhibition of Δ5,6-desaturase. This study provides a new target and a drug-like candidate for CM treatment.

UI MeSH Term Description Entries
D008826 Microbial Sensitivity Tests Any tests that demonstrate the relative efficacy of different chemotherapeutic agents against specific microorganisms (i.e., bacteria, fungi, viruses). Bacterial Sensitivity Tests,Drug Sensitivity Assay, Microbial,Minimum Inhibitory Concentration,Antibacterial Susceptibility Breakpoint Determination,Antibiogram,Antimicrobial Susceptibility Breakpoint Determination,Bacterial Sensitivity Test,Breakpoint Determination, Antibacterial Susceptibility,Breakpoint Determination, Antimicrobial Susceptibility,Fungal Drug Sensitivity Tests,Fungus Drug Sensitivity Tests,Sensitivity Test, Bacterial,Sensitivity Tests, Bacterial,Test, Bacterial Sensitivity,Tests, Bacterial Sensitivity,Viral Drug Sensitivity Tests,Virus Drug Sensitivity Tests,Antibiograms,Concentration, Minimum Inhibitory,Concentrations, Minimum Inhibitory,Inhibitory Concentration, Minimum,Inhibitory Concentrations, Minimum,Microbial Sensitivity Test,Minimum Inhibitory Concentrations,Sensitivity Test, Microbial,Sensitivity Tests, Microbial,Test, Microbial Sensitivity,Tests, Microbial Sensitivity
D003454 Cryptococcus A mitosporic Tremellales fungal genus whose species usually have a capsule and do not form pseudomycellium. Teleomorphs include Filobasidiella and Fidobasidium. Torula
D003455 Cryptococcus neoformans A species of the fungus CRYPTOCOCCUS. Its teleomorph is Filobasidiella neoformans. Blastomyces neoformans,Debaryomyces neoformans,Filobasidiella neoformans,Lipomyces neoformans,Saccharomyces neoformans,Torula neoformans,Torulopsis neoformans,Cryptococcus neoformans var. grubii
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000928 Antidepressive Agents Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems. Antidepressant,Antidepressant Drug,Antidepressant Medication,Antidepressants,Antidepressive Agent,Thymoanaleptic,Thymoanaleptics,Thymoleptic,Thymoleptics,Antidepressant Drugs,Agent, Antidepressive,Drug, Antidepressant,Medication, Antidepressant
D000935 Antifungal Agents Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. Anti-Fungal Agents,Antifungal Agent,Fungicides, Therapeutic,Antibiotics, Antifungal,Therapeutic Fungicides,Agent, Antifungal,Anti Fungal Agents,Antifungal Antibiotics
D016919 Meningitis, Cryptococcal Meningeal inflammation produced by CRYPTOCOCCUS NEOFORMANS, an encapsulated yeast that tends to infect individuals with ACQUIRED IMMUNODEFICIENCY SYNDROME and other immunocompromised states. The organism enters the body through the respiratory tract, but symptomatic infections are usually limited to the lungs and nervous system. The organism may also produce parenchymal brain lesions (torulomas). Clinically, the course is subacute and may feature HEADACHE; NAUSEA; PHOTOPHOBIA; focal neurologic deficits; SEIZURES; cranial neuropathies; and HYDROCEPHALUS. (From Adams et al., Principles of Neurology, 6th ed, pp721-2) Cryptococcal Meningitis,Granulomous Cerebral Cryptococcosis,Toruloma,Cerebral Cryptococcosis,Cerebral Cryptococcoses,Cerebral Cryptococcoses, Granulomous,Cerebral Cryptococcosis, Granulomous,Cryptococcal Meningitides,Cryptococcoses, Cerebral,Cryptococcoses, Granulomous Cerebral,Cryptococcosis, Cerebral,Cryptococcosis, Granulomous Cerebral,Granulomous Cerebral Cryptococcoses,Meningitides, Cryptococcal,Torulomas
D020280 Sertraline A selective serotonin uptake inhibitor that is used in the treatment of depression. Altruline,Apo-Sertraline,Aremis,Besitran,Gen-Sertraline,Gladem,Lustral,Novo-Sertraline,Rhoxal-sertraline,Sealdin,Sertraline Hydrochloride,Sertraline Hydrochloride (1S-cis)-Isomer,Zoloft,ratio-Sertraline,Apo Sertraline,Gen Sertraline,Hydrochloride, Sertraline,Novo Sertraline,Rhoxal sertraline,ratio Sertraline

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