Primaquine-thiazolidinones block malaria transmission and development of the liver exoerythrocytic forms.

BACKGROUND: Primaquine is an anti-malarial used to prevent Plasmodium vivax relapses and malaria transmission. However, PQ metabolites cause haemolysis in patients deficient in the enzyme glucose-6-phosphate dehydrogenase (G6PD). Fifteen PQ-thiazolidinone derivatives, synthesized through one-post reactions from primaquine, arenealdehydes and mercaptoacetic acid, were evaluated in parallel in several biological assays, including ability to block malaria transmission to mosquitoes. RESULTS: All primaquine derivatives (PQ-TZs) exhibited lower cell toxicity than primaquine; none caused haemolysis to normal or G6PD-deficient human erythrocytes in vitro. Sera from mice pretreated with the test compounds thus assumed to have drug metabolites, caused no in vitro haemolysis of human erythrocytes, whereas sera from mice pretreated with primaquine did cause haemolysis. The ability of the PQ-TZs to block malaria transmission was evaluated based on the oocyst production and percentage of mosquitoes infected after a blood meal in drug pre-treated animals with experimental malaria caused by either Plasmodium gallinaceum or Plasmodium berghei; four and five PQ-TZs significantly inhibited sporogony in avian and in rodent malaria, respectively. Selected PQ-TZs were tested for their inhibitory activity on P. berghei liver stage development, in mice and in vitro, one compound (4m) caused a 3-day delay in the malaria pre-patent period. CONCLUSIONS: The compound 4m was the most promising, blocking malaria transmissions and reducing the number of exoerythrocytic forms of P. berghei (EEFs) in hepatoma cells in vitro and in mice in vivo. The same compound also caused a 3-day delay in the malaria pre-patent period.

Sonochemistry: a good, fast and clean method to promote the synthesis of 5-arylidene-2,4-thiazolidinediones.

The efficient synthesis of sixteen 5-arylidene-2,4-thiazolidinediones by aldol condensation reaction of 2,4-thiazolidinedione, mono- and di-substituted arenealdehydes and KOH using ultrasound irradiation is reported. The desired compounds were obtained in a few min (10-30 min) with moderate to good yields (25-81%).

Antifungal activity of 3-(heteroaryl-2-ylmethyl)thiazolidinone derivatives.

Thiazolidinones, synthesized from multicomponent reactions of 2-heteroarylmethylamine, arenealdehydes and mercaptoacetic acid, have been tested against six yeasts, namely Candida albicans, C. parapsilosis, C. guilliermondii, Cryptococcus laurentii, Trichosporon asahii and Rhodotorula spp. The activities were expressed as minimum inhibitory concentrations (MIC) and the minimum fungicidal concentrations (MFC). The most affected yeasts were Rhodotorula spp and T. asahii. The cytotoxicities of the thiazolidinones against the fibroblast 3T3/NIH cell line are also described. The antifungal results and the low cytotoxicity of the compounds in this work provide good guides for the further development of active compounds.

Ultrasonics promoted synthesis of thiazolidinones from 2-aminopyridine and 2-picolilamine.

The efficient multicomponent synthesis of thiazolidinones from the reaction of arenealdehydes, mercaptoacetic acid and 2-picolilamine or 2-aminopyridine under ultrasound irradiation are reported. The reaction with 2-aminopyridine needs a Lewis acid catalysis to afford the corresponding 2-aryl-3-(pyridin-2-yl)-1,3-thiazolidin-4-ones. All novel compounds were identified and characterized by (1)H and (13)C NMR spectra. Applying the sonochemical methodology, two series of heterocyclic thiazolidinones were synthesized in good yields after short reaction times.

Efficient sonochemical synthesis of thiazolidinones from piperonilamine.

An efficient multicomponent reaction of arenealdehydes, mercaptoacetic acid and piperonilamine under ultrasound irradiation to afford 2-aryl-3-(piperonylmethyl)-1,3-thiazolidin-4-ones is reported. Applying this methodology, eleven heterocycles were synthesized and isolated in good yields after short reaction times.

4-(Pyrimidin-2-yl)-1-thia-4-aza-spiro-[4.5]decan-3-one.

The title compound, C(12)H(15)N(3)OS, features an envelope conformation for the 1,3-thia-zolidin-4-one ring with the S atom as the flap atom. The pyrimidine ring is almost orthogonal to the 1,3-thia-zolidin-4-one ring as indicated by the N-C-C-N torsion angle of -111.96 (18)°. Supra-molecular dimers are formed in the crystal structure through the agency of C-H⋯O contacts occurring between centrosymmetrically related mol-ecules. These are linked into supra-molecular tapes along [100] via C-H⋯S contacts.