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Chinese Journal of Chemistry 2013年第10期31卷 1305-1314页

作者： Wang Kang Xingqiong Du Lanzhi Wang Lijuan HU Yuhuan Dong Yanqing Bian Yuan Li College of Chemistry & Material Science Hebei Normal University Sho'iazhuang Hebei 050024 China College of Life Sciences Hebei Normal University Sho'iazhuang Hebei 050024 China Department of Chemistry Tangshan Normal University Tangshan Hebei 063000 China

Our studies examined the structural features responsible for the antifungal activity of 2-ethoxycarbonyl-1,5- benzothiazepine （7a）. Three series of 1,5-benzothiazepine derivatives were synthesized and screened for their antifungal activity. The results suggested that the ethoxycarbonyl group at the 2 position and the imine moiety on the seven-membered ring are essential for activity. The most potent of the synthesized analogues （7a, 7b） were further studied by evaluating their cytotoxicity and mode of action （for 7a）. The results showed that compounds 7a and 7b were relatively safe for BV2 cells, but compound 7a interfered with Cryptococcus neoformans cell wall integrity by increasing the chitinase activity. Therefore, compound 7a was considered safe as an antifungal agent for animal cells.

关键词： 1,5-benzothiazepines antifungal agents antifungal mechanism cytotoxicity structure-activity relationships

Controlling antifungal activity with light:Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors

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药学学报:英文版 2023年第7期13卷 3080-3092页

作者： Zhuang Li Na Liu Wanzhen Yang Jie Tu Yahui Huang Wei Wang Chunquan Sheng State Key Laboratory of Bioengineering Reactor And Shanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science&TechnologyShanghai 200237China School of Pharmacy Second Military Medical University(Naval Medical University)Shanghai 200433China Department of Pharmacology and Toxicology College of PharmacyAnd BIO5 InstituteUniversity of ArizonaTucsonAZ 85721USA

Invasive fungal infections(IFIs)have been associated with high mortality,highlighting the urgent need for developing novel antifungal strategies.Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14a-demethylase(CYP51)inhibitors.The photocaged triazoles completely shielded the CYP51inhibition.The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4%and 83.7%,respectively.Importantly,the shielded antifungal activity(MIC80≥64μg/m L)could be efficiently recovered(MIC80=0.5—8μg/m L)by light irradiation.The new chemical tools enable optical control of fungal growth arrest,morphological conversion and biofilm formation.The ability for highprecision antifungal treatment was validated by in vivo models.The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model.Overall,this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

关键词： antifungal agents Ergosterol biosynthesis Triazoles Photocaged Optical control

Small molecules for combating multidrug-resistant superbug Candida auris infections

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4056-4074页

作者： Jie Tu Na Liu Yahui Huang Wanzhen Yang Chunquan Sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China

Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.

关键词： Candidaauris antifungal agents Drug resistance Virulence factors antifungal targets

ERG3 and ERG11 genes are critical for the pathogenesis of Candida albicans during the oral mucosal infection

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International Journal of Oral Science 2018年第1期10卷 57-64页

作者： Yujie Zhou Min Liao Chengguang Zhu Yao Hu Ting Tong Xian Peng Mingyun Li Mingye Feng Lei Cheng Biao Ren Xuedong Zhou State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & West China Hospital of Stomatology Sichuan University

The hyphal development of Candida albicans(C.albicans) has been considered as an essential virulent factor for host cell damage.However, the missing link between hyphae and virulence of C.albicans is also been discovered. Here, we identified that the null mutants of ERG3 and ERG11, two key genes in ergosterol biosynthesis pathway, can form typical hyphae but failed to cause the oral mucosal infection in vitro and in vivo for the first time. In particular, the erg3Δ/Δ and erg11Δ/Δ strains co-cultured with epithelial cells significantly reduced the adhesion, damage, and cytokine(interleukin-1α(IL-1α)) production, whereas the invasion was not affected in vitro. Importantly, they were incapable of extensive hyphal invasion, formation of micro-abscesses, and tongue epithelium damage compared to wild type due to the decrease of the colonization and epithelial infection area in a murine oropharyngeal candidiasis model. The fluconazole(FLC), an antifungal targeted at ergosterol biosynthesis, relieved the epithelial infection of C.albicansin vitro and in vivo even under non-growth inhibitory dosage confirming the virulent contribution of ergosterol biosynthesis pathway. The erg3Δ/Δ and erg11Δ/Δ strains were cleared by macrophages similar to wild type, whereas their virulence factors including agglutinin-like sequence 1(Als1), secreted aspartyl proteinase 6(Sap6), and hyphal wall protein-1(Hwp1) were significantly reduced indicated that the non-toxicity might not result from the change on immune tolerance but the defective virulence. The incapacity of erg3Δ/Δ and erg11Δ/Δ in epithelial infection highlights the contribution of ergosterol biosynthesis pathway to C.albicans pathogenesis and fluconazole can not only eliminate the fungal pathogens but also reduced their virulence even at low dosage.

关键词： antifungal agents MOUSE MODEL RESISTANCE FLUCONAZOLE MECHANISMS EXPRESSION PROTEINASES PATHWAY YEAST

Phytochemical investigation of medicinally important plants of the Pothohar region of Pakistan

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Journal of Traditional Chinese Medicine 2020年第5期40卷 883-890页

作者： Amna Rabab Sobia Kanwal Tariq Mahmood Department of Plant Sciences Quaid-i-Azam UniversityIslamabad 45320Pakistan Department of Zoology University of GujratSub-Campus Rawalpindi 46000Pakistan

OBJECTIVE:To report the phytochemical composition(flavonoids,phenolics,saponins,tannins,and terpenoids)and biological activities(antioxidant,phytotoxic,cytotoxic,antifungal activities)of medicinally important plants of Pothohar region.METHODS:In the current study various qualitative and quantitative phytochemical tests were conducted to investigate the phytochemical composition of plant extracts prepared in benzene,chloroform and methanol.The same extracts were further utilized in different biological activities i.e.,antioxidant[total antioxidant capacity,total reducing power,and 2,2-diphenyl-1-picrylhydrazyl(DPPH)scavenging assay],phytotoxicity(Radish seed bioassay),brine shrimp cytotoxicity and antifungal activities(against four pathogenic fungal strains).RESULTS:Phytochemical analysis indicate flavonoids,phenolics,saponins,tannins and terpenoids were present in almost all plants however,maximum amount of total phenolic and flavonoid contents was reported in of Malva parviflora and Lepidium pinnatifidum.Extracts of Malva parviflora and Lepidium pinnatifidum also depicted the superlative antioxidant activity(total antioxidant capacity,total reducing power,and DPPH scavenging activity).Maximum fungal growth inhibition was demonstrated by extracts of Centaurea calcitropa,Vicia sativa and Malva parviflora.The maximum cytotoxicity was shown by the extracts of Centaurea calcitropa.Moreover,for phytotoxicity assay the highest allelopathic potential was exhibited by extracts of Lepidium pinnatifidum.Solvents prejudiced results;the best results were obtained by Methanol followed by Chloroform and Benzene.CONCLUSION:Centaurea calcitropa,Vicia sativa,Malva parviflora and Lepidium pinnatifidum are most promising medicinal plants of Pothohar region for future studies.

关键词： Centaurea Malva Cytotoxins antifungal agents Phytotoxicity Pothohar region

In vitro susceptibility testing of Aspergillus spp. against voriconazole, itraconazole, posaconazole, amphotericin B and caspofungin

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Chinese Medical Journal 2010年第19期123卷 2706-2709页

作者： SHI Jun-yan XU Ying-chun SHI Yi LU Huo-xiang LIU Yong ZHAO Wang-sheng CHEN Dong-mei XI Li-yan ZHOU Xin WANG He GUO Li-na Clinical Microbiology Laboratory Peking Union Medical College Hospital Peking Union Medical College China Academy of Medical Science Beijing 100730 China Department of Respiratory Nanjing General Hospital of Nanjing Military Command Nanjing Jiangsu 210002 China Clinical Laboratory Zhejiang-Provincial People's Hospital Hangzhou Zhejiang 310014 China Clinical Laboratory Shengjing Hospital of China Medical University Shenyang Liaoning 110001 China Clinical Microbiology Laboratory Jiangsu Province Hospital Nanjing Jiangsu 210029 China University Guangzhou Guangdong 510080 China Department of Dermatology Second Affiliated Hospital ofSun Yat-sen University Guangzhou Guangdong 510080 China Department of Respiratory Shanghai First People's Hospital Shanghai 200080 China

Background During recent years, the incidence of serious infections caused by opportunistic fungi has increased dramatically due to alterations of the immune status of patients with hematological diseases, malignant tumors, transplantations and so forth. Unfortunately, the wide use of triazole antifungal agents to treat these infections has lead to the emergence of Aspergillus spp. resistant to triazoles. The present study was to assess the in vitro activities of five antifungal agents （voriconazole, itraconazole, posaconazole, amphotericin B and caspofungin） against different kinds of Aspergillus spp. that are commonly encountered in the clinical setting. Methods The agar-based Etest MIC method was employed. One hundred and seven strains of Aspergillus spp. （5 species） were collected and prepared according to Etest Technique Manuel. Etest MICs were determined with RPMI agar containing 2% glucose and were read after incubation for 48 hours at 35℃. MIC50, MIC90 and MIC range were acquired by Whonet 5.4 software. Results The MIC90 of caspofungin against A. fumigatus, A. flavus and A. nidulans was 0.094 μg/ml whereas the MIC90 against A. niger was 0.19μg/ml. For these four species, the MIC90 of caspofungin was the lowest among the five antifungal agents. For A. terrus, the MIC90 of posaconazole was the lowest. For A. fumigatus and A. flavus, the MIC90 in order of increasing was caspofungin, posaconazole, voriconazole, itraconazole, and amphotericin B. The MIC of amphotericin B against A. terrus was higher than 32 μg/ml in all 7 strains tested. Conclusions The in vitro antifungal susceptibility test shows the new drug caspofungin, which is a kind of echinocandins, has good activity against the five species of Aspergillus spp. and all the triazoles tested have better in vitro activity than traditional amphotericin B.

关键词： aspergiUus antifungal agents drug resistance antifungal activity

Synthesis and in vitro Fungicidal Activity of a Series of Novel N-（Heterocycly）phthalimides

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Chinese Journal of Chemistry 2011年第3期29卷 515-520页

作者： Ban, Shurong Chen, Wenbin Xi, Zhen School of Pharmaceutical Science Shanxi Medical University Taiyuan Shanxi 030001 China Elemento-Organic Chemistry Institute State-Key Laboratory of Elemento-Organic Chemistry Nankai University Tianjin 300071 China

A series of novel phthalimides was prepared and tested for antifungal activity in vitro against seven phytopa- thogenic fungi： Rhizoctonia solani, Fusarium oxysporum f.sp. cucumerinum Owen., Botrytis cinerea, Fulvia fulva, Sclerotinia sclerotiorum de Bary, Phytophthora capsici, Botryosphaeria berengeriama. The results showed that those compounds holding the structure of 6-methylpyridin-2-yl exhibited good activity against Phytophthora capsici and Botrytis cinerea.

关键词： phthalimides synthesis biological activity antifungal agents

Guanidine derivative inhibits C. albicans biofilm growth on denture liner without promote loss of materials’ resistance

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Bioactive Materials 2020年第2期5卷 228-232页

作者： Isadora Martini Garcia Stéfani Becker Rodrigues Maria Eduarda Rodrigues Gama Vicente Castelo Branco Leitune Mary Anne Melo Fabrício Mezzomo Collares Dental Materials Laboratory Postgraduate Program in DentistrySchool of DentistryFederal University of Rio Grande Do SulRua Ramiro Barcelos2492Rio Branco90035-003Porto AlegreRSBrazil Ph.D.Program in Biomedical Sciences University of Maryland School of DentistryBaltimoreMD21201USA Operative Dentistry Division General Dentistry Department University of Maryland School of DentistryBaltimoreMD21201USA

To reduce the burden of denture stomatitis and oral candidiasis,an aqueous solution containing polyhexamethylene guanidine hydrochloride(PHMGH)was investigated as an antifungal disinfectant against the leading cause of these oral conditions,Candida albicans.The solutions formulated with concentrations ranging from 0.125 to 0.50 wt%enabled increasing disinfection at the initial 5min-contact with 72h-mature candida biofilms formed on denture liner specimens.After 10 min-contact,the solution at lower concentration has reached total fungal elimination.The results also indicated that the denture liners preserved their mechanical property after the maximum contact time with the solution at the highest tested concentration.The PHMGH aqueous solutions at 0.125 wt%could be applied to promote interim denture liner disinfection without promoting the loss of materials’mechanical property.

关键词： Dental materials Guanidine antifungal agents Candidiasis Denture liner

Effects of Two Curcuminoids on Candida albicans

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Chinese Herbal Medicines 2012年第3期4卷 205-212页

作者： ZHANG Da LUO Jiao-yang YAN Dan JIN Cheng DONG Xiao-ping XIAO Xiao-he China Military Institute of Chinese Materia Medica Military 302 HospitalBeijing 100039China Institute of Medicinal Plant Development Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100193China College of Pharmacy Chengdu University of Traditional Chinese MedicineChengdu 610075China

Objective To investigate and compare the action of curcuminoids on the causal pathogens of Candida albicans growth. Methods The effects of curcumin (CUR) and demethoxycurcumin (DMC) on C. albicans growth were first investigated and compared by microcalorimetry coupled with multiple analytical methods. The quantitative thermo-kinetic parameters obtained from these curves were analyzed to show difference of the actions. Results By analyzing the main parameters screened from principal component analysis together with 50% inhibiting concentration values, it was demonstrated that both CUR and DMC showed good antifungal activities and CUR was stronger. It was further concluded from structure-activity relationship that the existence of methoxy group might enhance lipophilicity of the mother nucleus, which made it easier for the molecular to enter into the cell membrane of fungi to inhibit its growth. Conclusion This study provides a new method for screening new antifungal agents with high efficacy and low toxicity. Meanwhile, it contributes to the application of curcuminoids as food additive, colorant, and drug. Microcalorimetry is real-time, online, and dynamic, and it could be used to characterize the subtle difference among the effects of synthetic and natural products on the vital process of fungi.

关键词： antifungal agents Candida albicans comparative study curcuminoids microcalorimetry

Topical Treatment of Infectious Vaginitis:Effects of Antibiotic,antifungal and Antiseptic Drugs on the Growth of Normal Vaginal Lactobacillus Strains

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Open Journal of Obstetrics and Gynecology 2015年第3期5卷 173-180页

作者： Christel Neut Francois Verrière Hans J.Nelis Tom Coenye Laboratoire de Bactériologie Clinique Faculté de Pharmacie Lille France Laboratoire Innotech International Arcueil France Laboratorium voor Farmaceutische Microbiologie Gent Belgium

Objectives: The balance of the vaginal ecosystem depends on lactobacilli whose biofilm protectsagainst microorganisms that are not normally present or are subdominant in vaginal flora. Vaginal?infection treatments should eliminate pathogens while preserving the?Lactobacillus?flora to prevent relapse or recurrence. The objective of this study was to determine the sensitivity of lactobacilli to antiseptics, antibiotics and antifungal agents used, alone or in combination, in the topical treatment of infectious vaginitis. Materials and Methods: The minimum inhibitory concentration (MIC) of 15 active ingredients and the minimum inhibitory dilution (MID) of 17 pharmaceuticals products were determined for three main?Lactobacillus?strains (L. crispatus,?L. gasseri?and?L. jensenii). Results: The MICs of the antibiotics and antifungal agents were above their critical concentrations in the three strains, contrary to the antiseptics. According to their MID, some pharmaceutical products, especially combinations, inhibit the growth of one or more strains at concentrations that can be found in the vaginal mucosa after application at the usual dosage. Conclusions: Certain topical anti-infective drugs may interfere with the growth of lactobacilli, worsening the vaginal flora imbalance. Maintaining vaginal flora balance should be a selection criterion when choosing an anti-infective therapy.

关键词： Lactobacillus Infectious Vaginitis Antiseptics Antibiotics antifungal agents