Maria Laura Schivo

Synthesis and antimycobacterial activity of some isonicotinoylhydrazones

Abstract Aseries of isonicotinoylhydrazones 2 were prepared by addition of some aryloxyacetonitriles with isonicotinoylhydrazine in basic medium. These compounds have been further reacted with pyridinecarboxaldehydes to give the corresponding pyridylmethyleneamino derivatives 3 – 5 . The new synthesized hydrazones and their pyridylmethyleneamino derivatives were tested for their activity against mycobacteria, Gram-positive and Gram-negative bacteria. The cytotoxicity was also tested. Several compounds showed a good activity against Mycobacterium tuberculosis H37Rv and some isonycotinoylhydrazones 2 showed a moderate activity against a clinically isolated M. tuberculosis which was isoniazid resistant.

Inhibition of cytokines expression in human microglia infected by virulent and non-virulent mycobacteria

The pathogenesis of tuberculosis (TBC) meningitis is still unknown. As shown by previous studies, human microglia can be the target of mycobacteria, but no data are available about their cellular response to infection. Consequently, we studied the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-10 in human microglia pure cultures infected with the two variants of Mycobacterium avium (domed-opaque (SmD) and transparent (SmT)) and with Mycobacterium tuberculosis. Results showed that microglia was productively infected by mycobacteria which could grow inside the cells. Mycobacteria internalization was more rapid for M. avium, but M. tuberculosis infection turned out to be more efficient due to the incorporation of densely packed bacteria. TNF-alpha expression was not affected by M. avium, whereas an increase followed by a decrease was observed in M. tuberculosis. Both IL-1 and IL-10 cytokine expression was rapidly inhibited by infection with the more virulent bacteria, whereas the non-pathogenic one had almost no effect. Also, the expression of the co-stimulatory molecule CD137, a member of tumor necrosis factor receptor family, was affected by infection with virulent mycobacteria. Our results show that microglia response to mycobacterial infection is modulated in correlation with virulence, mainly toward inhibition of inflammatory response. This observation might be one of the mechanisms by which non-pathogenic mycobacteria are quickly eliminated, explaining one of the bases of virulence.

Inhibition of poliovirus growth by 2-amino-4,6-dichloropyrimidine

La 2-amino-4,6-dicloropirimidina impedisce la formazione di proteine capsidiche capaci di organizzare con lo RNA virale particelle di poliovius complete ed infettanti.

Prevention by l-α-phosphatidylcholine of antifungal activity in vitro of liposome-encapsulated imidazoles determined by using time-killing curves

The antifungal activity of the imidazole derivatives miconazole and ketoconazole was reduced when they were entrapped in liposomal structures and significant differences were detected between small unilamellar vesicles (SUV) and multilamellar vesicles (MLV). To understand which component of liposomes interfered with the antifungal activity of miconazole and ketoconazole, we examined the influence of pure egg and soy L-alpha-phosphatidylcholine and cholesterol on activity against Candida albicans ATCC E10231 by time killing curves. Association of phospholipids-cholesterol-imidazole leads to an inhibitory effect on the antifungal activity comparable to that shown when miconazole or ketoconazole were entrapped in SUV liposomes or when miconazole and ketoconazole were incubated in the presence of L-alpha-phosphatidylcholine. The antifungal activity determined in the presence of cholesterol was comparable to that observed with the free drugs. Inhibition of the antifungal activity of miconazole and ketoconazole by phospholipids is dependent on the phospholipid concentration but is independent of the source of phospholipids (egg or soy). Cholesterol had no influence on the antifungal activity of the imidazoles, unlike the effect on other antifungal drugs, such as amphotericin B.

On the mechanism of the inhibitory action of 2-amino-4,6-dichloropyrimidine on poliovirus growth

La 2-amino-4,6-dicloropirimidina inibisce 10 sviluppo del Poliovirus rendendo i precursori capsidici incapaci di partecipare alla formazione di particelle infettanti. Questo effetto è irreversibile in quanto la sostanza è avidamente incorporata e ritenuta dalle cellule infette. Lantagonismo esercitato dallazione combinata di glutamina e cisteina fa ritenere che la pirimidina sostituita svolga il suo effetto interreagendo con questi due aminoacidi dopo la loro incorporazione nei precursori capsidici.

5-Iodo-2-deoxyuridine resistance of vaccinia viruses in cells endowed with thymidine kinase activity

La IUdR resistenza che alcuni DNA virus manifestano in cellule dotate di timidino-kinasi può essere dovuta ad una accentuata retroinibizione di questo enzima ad opera di TTP.

Mitostatic action of 4,6-dimethyl-2-amino-3,4,5-trimethoxyphenyl-pyrimidine on mammalian cells.

4, 6 dimethyl-2-amino-3, 4, 5-trimethoxyphenylpyrimidine arrests the mitotic cycle of mammalian cells in metaphase, both in vitro and in vivo. The mitostatic effect is promptly reverted by interruption of drug treatment.

Irreversible impairment produced by guanidine on the functions of poliovirus proteins

La guanidina altera irreversibilmente la capacità delle proteine capsidiche del poliovirus di partecipare alla formazione di particelle infettanti.