Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17ß-HSD10 modulators for Alzheimer's disease treatment.

Amyloid-beta peptide (Aß) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10). Altered enzyme function caused by the Aß-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17ß-HSD10 and potential drugs for Alzheimer's disease treatment: Design, synthesis and in vitro evaluation.

BACKGROUND: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) has been connected with the pathogenesis of Alzheimer's disease (AD). ABAD/ 17ß-HSD10 is a binding site for the amyloid-beta peptide (Aß) inside the mitochondrial matrix where it exacerbates Aß toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. METHODS: As ABAD's enzymatic activity is required for mediating Aß toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/ 17ß-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structure-activity relationship QSAR and pharmacophore studies have been performed. RESULTS AND CONCLUSIONS: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40µM) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.

Effect of Selected Pyrazine Derivatives on the Production of Phenolics and Rutin in Urtica dioica and Fagopyrum esculentum.

The effect of four pyrazine derivatives on the content of phenolic compounds in Urtica dioica L. and rutin in Fagopyrum esculentum Moench was studied. Pyrazine derivatives H1 and H2 were used on U. dioica, and derivatives S1 and S2 on F. esculentum, both separately and in combination with urea. The content of phenolic compounds in the stems of U. dioica after treatment with H2 at a concentration of 10(-3) M significantly increased compared with the control and to a lower concentration of the same pyrazine derivative. In the case of S1 and S2 for F. esculentum, rutin content also increased in stems, mainly after treatment together with urea. By contrast, rutin and phenolics contents in the leaves did not change in comparison with controls after application of H1, H2, S I and S2. Treatment with H1 and H2 in two chosen concentrations resulted in a significant increase in the net photosynthetic rate, transpiration rate and stomatal conductance. A slight increase in the rate of photosynthesis was observed also after application of variants of S1 and S1 with urea. Pyrazine derivatives did not show any effect on either the relative content of chlorophyll or chlorophyll fluorescence. A slight weight reduction of above ground biomass was shown only after application of Si and S2. Dark necrosis on the edges and center of the leaves was observed in all treated plants after pyrazine application. The results suggest that all the pyrazine derivatives possess herbicidal effects.

Development and validation of a FIA/UV-vis method for pK(a) determination of oxime based acetylcholinesterase reactivators.

Acetylcholinesterase reactivators (oximes) are compounds used for antidotal treatment in case of organophosphorus poisoning. The dissociation constants (pK(a1)) of ten standard or promising acetylcholinesterase reactivators were determined by ultraviolet absorption spectrometry. Two methods of spectra measurement (UV-vis spectrometry, FIA/UV-vis) were applied and compared. The soft and hard models for calculation of pK(a1) values were performed. The pK(a1) values were recommended in the range 7.00-8.35, where at least 10% of oximate anion is available for organophosphate reactivation. All tested oximes were found to have pK(a1) in this range. The FIA/UV-vis method provided rapid sample throughput, low sample consumption, high sensitivity and precision compared to standard UV-vis method. The hard calculation model was proposed as more accurate for pK(a1) calculation.