New alpha-(N)-heterocyclichydrazones: evaluation of anticancer, anti-HIV and antimicrobial activity.

A series of 3- and 5-methylthiophene-2-carboxaldehyde alpha-(N)-heterocyclichydrazones were synthesized and submitted to an in vitro investigation of their anticancer, anti-HIV and antimicrobial activities. Some of the newly synthesized compounds were found to possess antiproliferative properties, whereas no anti-HIV activity was seen; the most active of the series was the derivative 2i, which exhibited tumour growth inhibition activity against all cell lines displaying GI50 values between 1.63 and 26.5 microM. The title compounds were generally ineffective against Gram-positive and Gram-negative bacteria, while showed a moderate antifungal activity against C. albicans and A. fumigatus.

High affinity central benzodiazepine receptor ligands. Part 3: insights into the pharmacophore and pattern recognition study of intrinsic activities of pyrazolo[4,3-c]quinolin-3-ones.

Novel 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3-(3H)-ones (PQs) endowed with high affinity for central benzodiazepine receptor (BzR) were synthesized. In particular, 9-fluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (2(2)) showed binding affinity in the subnanomolar concentration range and proved to be in vitro a potent antagonist. This finding allowed the nature of the hydrogen bonding receptor site H(2) to be established, as located between the N-1 nitrogen of the PQ nucleus and the ortho position of the N-2-aryl group. [35S]tert-Butylbicyclophosphorothionate ([35S]TBPS) binding assays and electrophysiological measurements of the effects on GABA-evoked Cl(-) currents at recombinant human alpha(1)beta(2)gamma(2)(L) GABA(A) receptors, expressed in Xenopus laevis oocytes, were used to assess the intrinsic activities of a large series of PQs. With the aim of extracting discriminant information and distinguishing BzR ligands with different profiles of efficacy, 51 PQ derivatives, including full and partial agonists, antagonists, and inverse agonists, were analyzed in a multidimensional chemical descriptor space, defined by the lipophilicity parameter CLOG P and 3-D molecular WHIM descriptors, by means of principal component analysis, k-nearest neighbors (k-NN) method, and linear discriminant analysis (LDA). The classification methods were applied to subsets of pairs of efficacy classes, and lipophilicity and 3-D size descriptors were detected as the discriminant variables by a stepwise linear discriminant analysis. LDA proved to be superior to k-NN, especially in classifying PQ ligands (60-84% of success in prediction ability) into categories of efficacies which were contiguous and quite overlapped in the hyperspace of variables.

Specific targeting of acetylcholinesterase and butyrylcholinesterase recognition sites. Rational design of novel, selective, and highly potent cholinesterase inhibitors.

Tacrine-based AChE and BuChE inhibitors were designed by investigating the topology of the active site gorge of the two enzymes. The homobivalent ligands characterized by a nitrogen-bridged atom at the tether level could be considered among the most potent and selective cholinesterase inhibitors described to date. The nitrogen-containing homobivalent ligands 3e,g and the sulfur-containing 3h validated the hypothesis of extra sites of interaction in the AChE and BuChE active site gorges.

Synthesis and anti-tubercular evaluation of 4-quinolylhydrazones.

A series of 4-quinolylhydrazones were synthesized and tested against Mycobacterium tuberculosis H37Rv. Preparation of the title compounds was achieved by reaction of 4-quinolylhydrazine and aryl- or heteroaryl-carboxaldehyde. For the most of derivatives interesting antitubercular properties were showed; two compounds (3(2) and 3(25)), identified as the most active, were tested also against Mycobacterium avium.