Marcello Ferappi

Synthesis and antibacterial activity of pyridazino[4,3-b]indole-4-carboxylic acids carrying different substituents at N-2

The synthesis and the in vitro evaluation of antibacterial activity of new pyridazino[4,3-b]indole-4-carboxylic acids 2-4, 6 against some selected representative of Gram-positive and Gram-negative bacteria are reported. The role of the lipophilicity in the modulation of the antibacterial activity of the tested compounds is discussed. All the synthesized compounds appear quite weak against Gram-positive bacteria, whereas have no significant activity against Gram-negative bacteria. Only derivative 2g possesses an interesting activity against Gram-positive bacteria.

Lipophilicity measurements of benzenesulfonamide inhibitors of carbonic anhydrase by reversed-phase HPLC

Abstract The lipophilicity of 33 meta and para substituted benzenesulfonamides has been studied by reversed-phase high-performance liquid chromatography (RPLC) using methanol/water or acetonitrile/water as the mobile phases and μ-bondapak C 18 as the stationary phase. A linear relationship between the capacity factor (log k ′) and the volume fraction of the organic modifier (φ) has been established for each solute. The extrapolation of the retention to φ = 0 (0% of organic modifier) permitted the elimination of any selective and specific effects of organic modifier, to calculate log k w and finally to derive τ w for each substituent. The Hanschs π hydrophobic parameter was linearly correlated to τ w ( r = 0.953), but no improvement in the correlation equation was observed when τ w values obtained by adding silanol masking amines to the mobile phase were used. By introducing an indicator variable which takes into account the possibility of the substituent to make hydrogen bondings, a slight but significant improvement was instead observed. The replacement of π with τ w in the regression equation obtained in our recent quantitative structure-activity relationship (QSAR) study on carbonic anhydrase inhibition by benzenesulfonamides gives rise to a correlation equation with comparable statistical significance.

QSAR analysis of chemical and serum-catalyzed hydrolysis of phenyl ester prodrugs of nipecotic acid

Chemical and serum-catalyzed hydrolysis of an appropriately designed series of substituted X-phenyl esters of nipecotic acid were studied. A pseudo-first-order kinetics has been observed in the rates of both kinds of hydrolysis and for the serum-catalyzed hydrolysis the following quantitative structure-activity relationship was derived: log t12 = −0.99σ− − 0.21π + 2.25. In this equation t12 is the half-life, σ− is the “trough resonance” Hammett constant and π is the Hansch hydrophobic constant. The correlation equation pointed out the great influence of the electronic properties of X-substituents on the rate of hydrolysis which is only slightly influenced by the hydrophobicity of X. A group of suitably selected esters 4 was tested for antagonism of convulsions and death induced by bicuculline and a correlation between in vitro rates of enzymatic hydrolysis and anticonvulsant activity could be found. The results have been discussed in relation to the design of ester prodrugs of polar GABA-mimetics and other CNS-active agents.

Synthesis and antibacterial activity of 2-aryl-2,5-dihydro-3(3H)-oxo-pyridazino[4,3-b]indole-4-carboxylic acids.

The in vitro antibacterial and antifungal activities of a series of pyridazinoindolonic acids II against some selected representative of Gram-positive, Gram-negative bacteria and fungi have been investigated. Some interesting observations among the structural features necessary for high antibacterial activity are presented and discussed.

Synthesis of 12-mono- and di-substituted 8-aza-11-oxasteroids

The synthesis of unsaturated derivatives of 8-aza-11-oxa-17-oxo-gonane and D-homo-gonane carrying one or two functional substituents at C-12 is reported. The key step for the construction of the heterosteroid skeleton was the cyclocondensation reaction of aldol adducts 1, derived from 1,3-cycloalkanediones and diethyl 2-oxo-malonate, with tosyl chloride and isoquinoline.

PHTHALIMIDE DERIVATIVES OF PYRIMIDINE AND THIAZOLE HETEROCYCLES

The synthesis of some phthalimido-derivatives of the pyrimidine and thiazole ring systems is described. The functional groups have been suitably selected to enhance structural analogy with the pairs of pyrimidine and purine bases present in nucleic acids. In preliminary tests some of these compounds have shown inhibitory activity towards RNA polymerase reaction in vitro.