Renata Fringuelli

1,4-Benzothiazine and 1,4-Benzoxazine imidazole derivatives with antifungal activity: A docking study

We have recently described the synthesis and antifungal activity of a series of 1,4-benzothiazine and 1,4-benzoxazine imidazole derivatives that mainly showed in vivo activity against a murine experimental model of candidiasis but that very often lacked in vitro activity. Here, we report a docking study of a representative set of our molecules in a 3D model of CYP51 of Candida albicans (CA-CYP51). The model was constructed on the basis of the sequence homology relationship with the recently reported crystal structure of the CYP51 of Mycobacterium tuberculosis (MT- CYP51).

Anti-Candida albicans properties of novel benzoxazine analogues.

We previously reported that azole 1,4-benzothiazine derivatives have appreciable anti-Candida activity. In this study, we synthesized 1,4-benzoxazine analogues and examined their possible antifungal activity to further analyze the structure-activity relationships. Results of in vitro and in vivo experiments showed that 1,4-benzoxazine analogues show appreciable antifungal activity. In particular, they have significant capability to cure mice systemically infected with a lethal challenge of Candida albicans, as indicated by increased survival time paralleling reduction of colony forming units. Moreover, 1,4-benzoxazine derivatives also showed immunomodulating activity, as indicated by a significant increase of interleukin-12 and interferon-gamma production by splenocytes and reinforcement of a T helper type 1 protective immune response to C. albicans. In conclusion, the results demonstrate that replacement of sulfur by oxygen may improve immune response against C. albicans infection.

Azole derivatives of 1,4-benzothiazine as antifungal agents

A series of azole derivatives of 1,4-benzothiazine 7-14 was synthesized and evaluated for the in vitro and in vivo activity against Candida albicans. Secondary alcohol 10 and its ether derivative 13 showed very good efficacy against systemic candidiasis in a murine experimental model.

β-Keto esters from the rhodium(II) acetate catalysed conversion of α-diazo-β-hydroxy esters

A new and efficient procedure for the transformation of α-diazo-β-hydroxy esters into the corresponding β-keto esters, which involves the use of Rh2(OAc)4, is described.

Reduction of α-diazo-β-hydroxy esters to β-hydroxy esters: application in one of two convergent syntheses of a (22S)-22-hydroxy bile acid from fish bile and its (22R)-epimer

α-Diazo-β-hydroxy esters (3) prepared by condensation of aldehydes (1) with ethyl (lithio) diazoacetate (2) are reduced with 5% palladium over charcoal in methanol into the corresponding β-hydroxy esters (5) in high yield. This sequence is applied to a new synthesis of haemulcholic acid (14c), a (22S)-22-hydroxy bile acid from fish bile and its (22R)-epimer (14d). A convergent synthesis of (14c), a (22S)-22-hydroxy bile acid from fish bile and its (22R)-epimer (14d). A convergent synthesis of (14c) and (14d) involves, as a key step, the dirhodium (II) tetra-acetate conversion of (12) into the corresponding β-keto ester (13).

An efficient procedure for the regiospecific preparation of d-homo-steroid derivatives

alpha-Diazo-beta-hydroxy esters 3, obtained by condensation of ketones 1 with ethyl diazo(lithio)acetate 2, are efficiently converted into the corresponding beta-ketoesters 4 by exposure to dirhodium (II) tetraacetate. Application of this two-step sequence to 3 beta-acetoxy-5-androstene-17-one 5b and to 3-acetoxy estrone 10b afforded regiospecifically and in very high overall yield the corresponding ethyl 17a-oxo-D-homo-steroid-17-carboxylates 7a,b and 12a,b, which were decarboalkoxylated to give, respectively, 3 beta-hydroxy-D-homo-5-androstene-17a-one 8 and D-homoestrone 13.

A new synthesis of β-damascone

Abstract A new synthetic route to β-damascone (7) starting from β-cyclocitral (1) is described. The crucial intermediate 9-oxo-dihydro-β-damascone (3) is prepared in two steps by treatment of (1) with 1-diazo-1-lithioacetone followed by the rhodium (II) acetate conversion of 3-diazo-4-hydroxy-4(2,2,6-trimetylcyclohex-6-enyl) butan-2-one (2) thus formed to (3).

1,4-Benzothiazine analogues and apoptosis: Structure-activity relationship

We have previously shown 1,4-benzothiazine (1,4-B) derivatives induce thymocyte apoptosis in vitro and thymus cell loss in vivo. Apoptosis is mediated through a complex of biochemical events including phosphatidylcholine specific-phospholipase C (PC-PLC) activation, acidic sphingomyelinase (aSMase) activation and ceramide generation, caspase-8 and caspase-3 activation. As preliminary analysis of the structure-activity relationship (SAR) suggested some structural features were responsible for apoptosis, we synthesised several derivatives and tested for apoptosis activity at equimolar concentrations. In particular, we synthesised analogues that differed in the nature of skeleton (1,4-benzothiazine, 1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline) and in the nature of side chain (imidazole, benzimidazole or piperazine as azole substituent; presence, absence or transformation of alcoholic group). Results of apoptosis induction indicate that transforming the 1,4-benzothiazine skeleton into 1,2,3,4-tetrahydroquinoline does not result in significant change. Transformation into 1,4-benzoxazine decreased activity. Replacing imidazole at the side chain with different piperazines also decreased activity while replacing it with benzimidazole does not change apoptotic activity. Finally, removal of the alcoholic group by dehydration to olefin, or by transforming it into ether, increased activity. Moreover, in an attempt to analyse further the SAR characteristics that are responsible for 1,4-B-activated apoptosis we tested the effect on caspase-8,-9 and-3 activation. 1,4-B analogues activate caspases and the structural requirements correlate with those responsible for apoptosis induction.

An improved two-step route for the preparation of β-diketones from aldehydes and its application to the synthesis of β-damascone

α-Diazo-β-hydroxyketones, obtained by condensation of aldehydes with 1-diazo-1-lithioacetone, are efficiently transformed into the corresponding β-diketones by exposure to rhodium(II) acetate. The sequence is applied to a new synthesis of β-damascone (10).

Oxime and Oxime Ether Derivatives of 1,4- Benzothiazine Related to Oxiconazole

The synthesis, in vitro antifungal activity, and molecular docking experiments of some oxime and oxime ether derivatives of azole 1,4‐benzothiazine are reported herein, with the aim of evaluating the influence of a partially constrained scaffold that is structurally related to Oxiconazole and bearing the 1,4‐benzothiazine moiety, on the inhibition of Candida albicans CYP51.