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Design, synthesis and biological evaluation of novel diazaspirodecanone derivatives containing piperidine-4-carboxamide as chitin synthase inhibitors and antifungal agents. 2021

Qinggang Ji, and Bing Li, and Yiwen Chu, and Hu Wu, and Chuanbiao Du, and Yajie Xu, and Yangli Shen, and Junfeng Deng
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China. Electronic address: jiqing@swu.edu.cn.

A series of novel 2-oxo-(1-oxo-2,8-diazaspiro[4.5]decane-8-yl)ethylpiperidine carboxamide derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS spectroscopy. All eighteen newly prepared compounds were evaluated for their inhibition against chitin synthase (CHS) and antifungal activities in vitro. The enzyme assay revealed that compound 5h showed excellent inhibitory activity against CHS with IC50 value of 0.10 mM, and the compounds 5b, 5d and 5q showed good inhibition against chitin synthase with IC50 values of 0.13 mM, 0.18 mM and 0.15 mM, respectively, while IC50 value of ployoxin B was 0.08 mM. Meanwhile, the others of these compounds exhibited moderate inhibition potency against chitin synthase. The antifungal assay showed compound 5h had excellent antifungal activity compared with the control drugs fluconazole and polyoxin B against these tested strains including C. albicans, A. fumigatus, C. neoformans and A. flavus. Its excellent antifungal activity was consistent with its excellent chitin synthase inhibition. Compound 5k and 5l against C. albicans were comparable with fluconazole, and they showed strong antifungal potency against A. flavus with MIC values of 0.07 mmol/L and 0.13 mmol/L respectively. Compound 5m had similar MIC value against A. fumigatus to fluconazole. The phenomenon that compounds 5b, 5d and 5q that showed good enzymatic inhibition didn't exert good antifungal activity, while compounds 5k, 5l and 5m that showed moderate chitin synthase inhibition exhibited excellent antifungal activity was discussed. Furthermore, the trial of drug combination showed that compounds had synergistic effects or additive effects with fluconazole against tested fungi which also verified that these designed compounds targeted different targets from that of fluconazole. Additionally, the antibacterial trial showed that all synthesized compounds had little potency against tested bacteria strains. These results indicated that the designed compounds were potential chitin synthase inhibitors and had selectively antifungal activities.

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
D010880 Piperidines A family of hexahydropyridines.
D002175 Candida A genus of yeast-like mitosporic Saccharomycetales fungi characterized by producing yeast cells, mycelia, pseudomycelia, and blastophores. It is commonly part of the normal flora of the skin, mouth, intestinal tract, and vagina, but can cause a variety of infections, including CANDIDIASIS; ONYCHOMYCOSIS; VULVOVAGINAL CANDIDIASIS; and CANDIDIASIS, ORAL (THRUSH). Candida guilliermondii var. nitratophila,Candida utilis,Cyberlindnera jadinii,Hansenula jadinii,Lindnera jadinii,Monilia,Pichia jadinii,Saccharomyces jadinii,Torula utilis,Torulopsis utilis,Monilias
D002687 Chitin Synthase An enzyme that converts UDP glucosamine into chitin and UDP. EC 2.4.1.16. Chitin-UDP Acetylglucosaminyltransferase,Chitin Synthase 1,Chitin Synthetase 2,trans-N-Acetylglucosaminosylase,Acetylglucosaminyltransferase, Chitin-UDP,Chitin UDP Acetylglucosaminyltransferase,trans N Acetylglucosaminosylase
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
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
D001230 Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family Trichocomaceae.
D001372 Aza Compounds Organic chemicals where carbon atoms have been replaced by nitrogen atoms. Compounds, Aza
D012441 Saccharomyces cerevisiae A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement. Baker's Yeast,Brewer's Yeast,Candida robusta,S. cerevisiae,Saccharomyces capensis,Saccharomyces italicus,Saccharomyces oviformis,Saccharomyces uvarum var. melibiosus,Yeast, Baker's,Yeast, Brewer's,Baker Yeast,S cerevisiae,Baker's Yeasts,Yeast, Baker

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