Σύγχρονες προσεγγίσεις στο σχεδιασμό και στην ανάπτυξη αντιφλεγμονωδών ενώσεων
Creators: name: Ζιάκας, Γεώργιος Ν.
Publisher: name: Aristotle University of Thessaloniki
Year: 2007
Subjects: Δότες μονοξειδίου του αζώτου
Αντιοξειδωτικά
Εστέρες του τολφαιναμικού οξέος
Παράγωγα 2,6-Δ1-ΤΕΡΤ-Βουτυλοφαινόλης
Αναστολή κυκλοοξυγονάσης/λιποξυγονάσης
Nitric oxide donors
Antioxidants
Tolfenamic acid esters
2,6-DI-Butylphenol derivatives
Cyclooxygenase/Lipoxygenase inhibition

description: Στην παρούσα εργασία αναφέρουμε τη σύνθεση 26 ενώσεων, 13 από τις οποίες είναι καινούριες. Σχεδιάσαμε και συνθέσαμε 7 καινούρια παράγωγα του τολφαιναμικού οξέος (Τ.Ο.) τα οποία έχουν ομάδα δότη ΝΟ (ενώσεις 6-12) και 6 καινούρια παράγωγα της 2,6-δι-tert-βουτυλοφαινόλης (ενώσεις 20, 22-26) τα οποία είναι αμίνες και αμίδια της θειομορφολίνης, της μορφολίνης και της προλίνης. Η ένωση 21 ήταν ήδη γνωστή. Αυτές οι ενώσεις δοκιμάσθηκαν in vitro και in vivo όσον αφορά την ικανότητά τους να αποδεσμεύουν ΝΟ (παράγωγα του Τ.Ο.), την αντιοξειδωτική και την αντιφλεγμονώδη δράσης τους. Τέλος, τα παράγωγα 7 και 22, δύο από τα πιο δραστικά που συνετέθησαν, εξετάσθηκαν σε σχέση με τις μητρικές ενώσεις, το Τ.Ο. και το BHT αντίστοιχα, όσον αφορά την τοξικότητα τους. Η in vivo αντιφλεγμονώδης δράση όλων των τελικών προϊόντων, του Τ.Ο. και του BHT εκτιμήθηκε με χρήση του προτύπου επαγωγής οιδήματος σε άκρο πόδα επίμυος από καραγενίνη
description: In the present thesis we report the synthesis of 26 compounds, 13 of which are novel. Bearing in mind the above studies, we designed and synthesized 7 new derivatives of tolfenamic acid (T.A.) with a NO-donating moiety (compounds 6-12) and 6 new derivatives of 2,6-di-tert-butylphenol (compounds 20, 22-26) which are amines or amides of substituted thiomorpholine, morpholine and proline. We have previously found that some substituted morpholines possess anti-inflammatory and antioxidant properties thus, we decided to use similar structures as part of our molecules. Compound 21, which has been prepared earlier by another syntetic route, is included in our series and tested for its activity. The formation of T.A. derivatives (compounds 6-12) was a two step procedure, with the exception of compounds 11 and 12 which were prepared from commercially available 4- and 3-nitro-phenylethyl alcohols, respectively. Two different methods were used for preparing the nitrooxyalcohols. The reaction of silver nitrate with the appropriate alkyl chloride, yielding the nitric ester and silver chloride, or of nitric acid with the corresponding alkyl alcohol have been applied. The second method was found to be the most favorable, due to better yields and lower cost. The final step in the synthesis of compounds 6-12 was an esterification of T.A. with the corresponding nitrooxyalcohol in the presence of 2,2-dicyclohexylcarbodiimide and catalytic amounts of 4-dimethylaminopyridine. The BHT derivatives (compounds 20-26) were obtained by the reaction of the alkyl or akyl chlorides of 2,6-di-tert-butylphenol with the corresponding amine in the presence of equimolar amounts of triethylamine. For the amides 21, 23 and 26, direct amidation of the carboxylic group of 3,5-di-tert-butyl-4-hydroxybenzoic acid in the presence of 2,2-dicyclohexylcarbodiimide could not be accomplished. The intermediate amines were prepared by using various methods.These compounds were tested in vitro and in vivo for the evaluation of their antioxidant, NO-donating (only the TA derivatives that are NO donors) and anti-inflammatory activities. Finally, the toxicity of compounds 7 and 22, two of the most active compounds, was examined, in relation to the parent molecules, T.A. and BHT respectively. The in vivo anti-inflammatory activity of all final compounds, T.A. and BHT was evaluated by using the carrageenan induced paw edema method in rats