Bulky 1,4-benzoxazine derivatives with antifungal activity

被引:30
作者
Fringuelli, Renata [1 ]
Giacche, Nicola [1 ]
Milanese, Lara [1 ]
Cenci, Elio [2 ]
Macchiarulo, Antonio [1 ]
Vecchiarelli, Anna [2 ]
Costantino, Gabriele [1 ]
Schiaffella, Fausto [1 ]
机构
[1] Univ Perugia, Dipartimento Chim & Tecnol Farmaco, I-06100 Perugia, Italy
[2] Univ Perugia, Dipartimento Med Sperimentale & Sci Biochim, I-06100 Perugia, Italy
关键词
Azole antifungals; Ketoconazole-like drugs; 1,4-Benzoxazine; CA-CYP51; inhibitors; CELL TRANSPLANT RECIPIENTS; IN-VITRO; MICROBIOLOGICAL EVALUATION; IMIDAZOLE DERIVATIVES; CANDIDA; 1,4-BENZOTHIAZINE; KETOCONAZOLE; INFECTIONS; DESIGN; VIVO;
D O I
10.1016/j.bmc.2009.04.051
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
For many years the development of new azole antifungals has been quite empirically based. More recently, the publication of the crystal structure of CYP51 of Mycobacterium tuberculosis (MT-CYP51) provided new opportunities to rationalize the knowledge about antifungal action of this class of compounds. Recent studies reported that a 'channel 2 opened' conformation of the enzyme could better explain the interaction with ketoconazole (KTZ)-like drugs. Conformational changes were made on our model of Candida albicans CYP51 (CA-CYP51) previously reported and docking experiments were performed. The results allowed new KTZ analogues to be designed, by predicting that the 1,4-benzoxazine moiety could replace the KTZ aryl-piperazinyl chain. The synthesis of derivatives 12 and 13 was planned. The in vitro antifungal activity was evaluated against different Candida species and low and high capsulated strains of Cryptococcus neoformans. Since the in vitro activity do not necessarily correlate with the in vivo antifungal activity the newly synthesized compounds were also tested in a murine model of systemic C. albicans infection. The therapeutic effect was evaluated in terms of animal survival and of fungal growth in the kidneys, the target organ in systemic candidiasis. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:3838 / 3846
页数:9
相关论文
共 28 条
[1]  
*ACC, CER 2
[2]   CORRELATION BETWEEN IN-VITRO AND IN-VIVO ACTIVITY OF ANTIFUNGAL AGENTS AGAINST CANDIDA SPECIES [J].
ANAISSIE, EJ ;
KARYOTAKIS, NC ;
HACHEM, R ;
DIGNANI, MC ;
REX, JH ;
PAETZNICK, V .
JOURNAL OF INFECTIOUS DISEASES, 1994, 170 (02) :384-389
[3]  
[Anonymous], 2002, P NAT COMM CLIN LAB
[4]   Review of epidemiology, diagnosis, and treatment of invasive mould infections in allogeneic hematopoietic stem cell transplant recipients [J].
Bhatti, Zahida ;
Shaukat, Aasma ;
Almyroudis, Nikolaos G. ;
Segal, Brahm H. .
MYCOPATHOLOGIA, 2006, 162 (01) :1-15
[5]   EVIDENCE FOR MACROPHAGE-MEDIATED PROTECTION AGAINST LETHAL CANDIDA-ALBICANS INFECTION [J].
BISTONI, F ;
VECCHIARELLI, A ;
CENCI, E ;
PUCCETTI, P ;
MARCONI, P ;
CASSONE, A .
INFECTION AND IMMUNITY, 1986, 51 (02) :668-674
[6]   Candidemia in the 21st century [J].
Chang, Amy ;
Neofytos, Dionissios ;
Horn, David .
FUTURE MICROBIOLOGY, 2008, 3 (04) :463-472
[7]   Anti-Candida albicans properties of novel benzoxazine analogues [J].
Fringuelli, R ;
Pietrella, D ;
Schiaffella, F ;
Guarraci, A ;
Perito, S ;
Bistoni, F ;
Vecchiarelli, A .
BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (06) :1681-1686
[8]   Azole derivatives of 1,4-benzothiazine as antifungal agents [J].
Fringuelli, R ;
Schiaffella, F ;
Bistoni, F ;
Pitzurra, L ;
Vecchiarelli, A .
BIOORGANIC & MEDICINAL CHEMISTRY, 1998, 6 (01) :103-108
[9]   BIS[[4-(2,2-DIMETHYL-1,3-DIOXOLYL)]METHYL]-CARBODIIMIDE (BDDC) AND ITS APPLICATION TO RESIDUE-FREE ESTERIFICATIONS, PEPTIDE COUPLINGS, AND DEHYDRATIONS [J].
GIBSON, FS ;
PARK, MS ;
RAPOPORT, H .
JOURNAL OF ORGANIC CHEMISTRY, 1994, 59 (24) :7503-7507
[10]   Introduction of a hydroxy group at the para position and N-iodophenylation of N-arylamides using phenyliodine(III) bis(trifluoroacetate) [J].
Itoh, N ;
Sakamoto, T ;
Miyazawa, E ;
Kikugawa, Y .
JOURNAL OF ORGANIC CHEMISTRY, 2002, 67 (21) :7424-7428