Fausto Schiaffella

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.

(1,4-Benzothiazinyloxy)alkylpiperazine derivatives as potential antihypertensive agents.

A series of compounds having a piperazine moiety variously linked to the benzothiazine nucleus were synthesized and evaluated for their in vitro alpha-adrenoceptor affinity by radioligand receptor binding assays. Some compounds bearing a oxyalkyl-(2-methoxyphenyl)piperazine side chain were good alpha1-adrenoreceptor ligands.

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.

One-Pot Synthesis of Rufloxacin

Abstract Rufloxacin (MF-934) was prepared in one-pot synthesis in 61% yield by treatment of the 2,3,5-trifluoro-4-(4-methyl-1-piperazinyl)-benzoyl acetate, first with N,N-dimethylformamide dimethyl acetal, then with 2-aminoethanethiol, followed by cyclization and hydrolysis.

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.

Synthesis and β-adrenergic blocking activity of 1,4-benzothiazine oxime ethers

Abstract Synthesis of 6-, 7-, 8-acetimidoyloxypropanolamines of 3,4-dihydro-3-oxo-2 H-1,4-benzothiazine and 8-iminoxypropanolamines of 3,4,5,6,7,8-hexahydro-3-oxo-2 H-1,4-benzothiazine are reported. All of the synthesized compounds were tested in vitro for their ability to displace [3H]dihydroalprenolol from turkey erythrocyte membranes and in vivo for their β-adrenoceptor blocking activity by the inhibition of isoprenaline-induced tachycardia and compared with the corresponding oxypropanolamines which we had previously described as β-blockers.

Symbiotic approach to drug design: N-[(4-chloro-3-sulfamoylbenzamido)-ethyl]propanolamine derivatives as β-adrenergic blocking agents with diuretic activity

Abstract A series of oxypropanolamines and iminoxypropanolamines, in which the aminic substituent was the 2-(4-chloro-3-sulfamoylbenzamido)-ethyl group, were synthesized as potential β-blocker/diuretic agents. All of these compounds were tested for β 1 -adrenoceptor affinity and β-blocking potency. For the most active compounds, diuretic and antihypertensive properties as well as affinity for α 1 -adrenoceptors were also investigated. Compounds 4 and 10 were found to display contemporaneously β-blocking, diuretic and antihypertensive activities.

Synthesis and β-Adrenergic Blocking Activity of Oxypropanolamines of 3,4-Dihydro-3-oxo-2H(1,4)benzothiazine.

The synthesis of a series of oxypropanolamines of 3,4-dihydro-3-oxo-2H(1,4)benzothiazine is reported. Some of these compounds proved more potent than propranolol and carteolol as beta-adrenergic blocking agents in in vitro tests. The 8-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-3-oxo-2H(1,4) benzothiazine fumarate (XVI a), which gave better results, confirmed its remarkable activity in in vivo tests.