AIELLO, Stefania

LICATA, Anna

López Cara, L

VENTURELLA, Fabio

Archivio istituzionale della ricerca - Università di Palermo

86° CONGRESSO NAZIONALE SIBS - PALERMO 24-25 OTTOBRE 2013    P05 - SYNTHESIS AND SAR STUDIES OF  NEW 3-METHYL-5-(5-PROPYL-1H-1-R'-3-PYRAZOLYL)-1H-1-R-4-NITROSOPYRAZOLES AS ANTIMICOTIC AGENTS.   S. Aiello1*; L. C. López-Cara 2, F. Venturella3 and A. Licata4  1Unità Didattico Scientifica di Fisiologia e Farmacologia, Dip. DIGSPO, Università di Palermo  2Dpto. Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada C/ Campus cartuja s/n CP.18071, Granada, Spain 3Dipartimento  Scienze e Tecnologie Biologiche,Chimiche e Farmaceutiche (STEBICEF), Unipa 4Sezione di Gastroenterologia, DiBiMIS;  Università di Palermo *Corresponding author: Stefania Aiello, Phone:+39 091 6236410 e-mail: stefania.aiello@unipa.it  Many ubiquitous yeast are primarily pathogens for immunocompromised patients, individuals with AIDS and organ transplanted are at high risk of cryptococcosis and candidiasis. In this setting, fungal infections are particularly difficult to treat because antifungal therapy usually does not eradicate the infection and require lifelong treatment with antifungal drugs. Consequently, the need for novel antifungal agents for opportunistic infections is apparent in light of significant problems associated with current drugs and makes the development of new drug entities all more urgent. We have reported that some 3-(3-alkyl-4-nitroso-1H-5-pyrazolyl)-5-R-isoxazoles [1] and the isomeric 5-(1-alkyl-4-nitroso-1H-3-pyrazolyl)-3-R-isoxazoles [2] showed in vitro potent antifungal activity at non cytotoxic concentrations. This antifungal activity was correlated to: 1) the interaction of the isoxazolic nitrogen with the alkyl group bound to the pyrazolyl nitrogen; 2) the cis or trans configuration adopted by the nitroso group with respect to the alkyl chain bound to the pyrazolic nitrogen and perpendicularly folded to the molecular plane. To verify this hypothesis, we synthesized compounds in which the isoxazole was substituted by a pyrazole moiety, leading to the new isomeric series I and II.      R’:CH2CH2CH3; R:  a=H, b=CH3; c=CH2CH3  The title compounds  tested in vitro for antifungal activity against C. Neoformans and C. Krusei, displayed an interesting antifungal activity, in particular compound Ib was 2 and 32 fold more potent than Amphotericin B and Fluconazole, respectively, against C. krusei, fungus with intrinsic resistance to many of antifungal azoles These results suggest that, depending on the heterocyclic molecule bound to the 5 position of 1H-1-R-4-nitrosopyrazoles, it is possible to modulate the antifungal activity of 4-nitrosopyrazoles. In vitro metabolism studies and in vivo assay are in progress for all described compounds.  NNNNON CH3H3CR'R NNNNON CH3H3CR'RR'= Me, Et; R=H, Me, Et I II86° CONGRESSO NAZIONALE SIBS - PALERMO 24-25 OTTOBRE 2013    References   1. Aiello, E.; Aiello, S.; Mingoia, F.; Bacchi, A.; Pelizzi, G.; Musiu, C.; Setzu, M. G.; Pani, A.; La Colla, P. and Marongiu, M. E.. Synthesis and Antimicrobial Activity of new 3-(1-R-3-methyl-4-nitroso-1H-5-pyrazolyl)-5-methylisoxazole derivatives. Bioorganic and Medicinal Chemistry, 2000, 8, 2719-2728. 2. Stefania Aiello; Enrico Aiello, Marica Orioli, Marina Carini, 3-(1-R-3-methyl-4-nitroso-1H-5-pyrazolyl)-5-methylisoxazoles: a new class of antifungal compounds. In vitro metabolism by rat liver:LC and LC-MS studies. Convegno Nazionale SCI, Sorrento 18-22 Settembre 2002. 3. S. Aiello, E. Aiello and M.E. Milici, Synthesis and Antifungal Activity of new 3(5)-methyl-5(3)-(2-thiophenyl) and -(2-quinolyl)-1H-1-R-4-nitrosopyrazoles. Part V. Polish-Austrian-German-Hungarian-Italian Joint Meeting on Medicinal Chemistry, Krakow, October 15-18, 2003. 4. Stefania Aiello, Antonio Macchiarulo, Maria Milici and Enrico Aiello, Sintesi e studi QSAR di nuovi derivati 3(5)-(2-X)-1R-1H-4-nitrosopirazoli: una classe di composti con potente attività antifungina in vitro. Parte VI. XVII Convegno Nazionale della Divisione di Chimica Farmaceutica della SCI, Pisa 6-10 settembre 2004.   

SYNTHESIS AND SAR STUDIES OF NEW 3-METHYL-5-(5-PROPYL-1H-1-R'-3-PYRAZOLYL)-1H-1-R-4-NITROSOPYRAZOLES AS ANTIMICOTIC AGENTS.

https://iris.unipa.it/retrieve/handle/10447/84648/94708/aiello1SIBS2013.pdf

SYNTHESIS AND SAR STUDIES OF NEW 3-METHYL-5-(5-PROPYL-1H-1-R'-3-PYRAZOLYL)-1H-1-R-4-NITROSOPYRAZOLES AS ANTIMICOTIC AGENTS.

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