title: Novel ketoconazole analogues based on the replacement of 2,4-dichlorophenyl group with 1,4-benzothiazine moiety: design, synthesis, and microbiological evaluation.
abstract: As a part of a program to develop novel antifungal agents, new compounds which incorporate the 1,4-benzothiazine moiety into the structure of ketoconazole (KTZ) were prepared. These compounds were computationally investigated to assess whether the 1,4-benzothiazine moiety was a suitable bioisosteric replacement for the 2,4-dichlorophenyl group of KTZ in order to obtain a more potent inhibition of CYP51 enzyme of Candida albicans. Results of preliminary microbiological studies show that the racemic cis-7 analogue has a good in vivo activity, comparable to that of KTZ, but the best activity was observed in the racemic trans-7 analogue.
authors.affiliation: Department of Drug Chemistry and Technology, University of Perugia, Perugia 06100, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Schiaffella
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Lara
authors.initials: L
authors.lastname: Milanese
authors.forename: Anna
authors.initials: A
authors.lastname: Vecchiarelli
authors.forename: Renata
authors.initials: R
authors.lastname: Fringuelli
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D002177:Candidiasis / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry; D007159:Immunologic Tests; D007654:Ketoconazole / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry*
chemical_list: C446962:1,4-benzothiazine; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D006843:Hydrocarbons, Chlorinated; D013843:Thiazines; C465525:cytochrome P-450 CYP51, Candida albicans; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole