New 5-substituted-1-(2-hydroxybenzoyl)-benzotriazoles, potassium channel activators. IV

• Published in: Farmaco (Società chimica italiana : 1989) Vol. 56; no. 11; pp. 827 - 834
• Main Authors: Biagi, Giuliana, Giorgi, Irene, Livi, Oreste, Scartoni, Valerio, Barili, Pier Luigi, Calderone, Vincenzo, Martinotti, Enrica
• Format: Journal Article
• Language: English
• Published: Lausanne Elsevier SAS 01-11-2001; Elsevier Science
• Subjects: Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiology; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Benzotriazoles; Biological and medical sciences; Cardioprotection; Cardiovascular system; Chlorophenols - chemical synthesis; Chlorophenols - chemistry; Chlorophenols - pharmacology; In Vitro Techniques; Male; Medical sciences; Miscellaneous; Molecular Structure; Pharmacology. Drug treatments; Potassium channels; Potassium Channels - agonists; Rats; Rats, Wistar; Salicylanilides; Structure-Activity Relationship; Vasodilation - drug effects; Vasodilator activity; Vasodilator Agents - chemical synthesis; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacology; Salicylanilides; Vasodilator activity; Cardioprotection; Potassium channels; Benzotriazoles; Heart; Vasodilator agent; Rat; Arrhythmia; Nitrogen heterocycle; Cardiovascular disease; Smooth muscle; Potassium channel agonist; Isolated organ; Prevention; Reperfusion; Ischemia; Structure activity relation; Heart disease; Blood vessel; Bicyclic compound; Aorta; Complication; Aromatic compound; Mechanism of action; Chemical synthesis; Rodentia; Cardioprotective agent; In vitro; Vertebrata; Mammalia; Animal; Phenols
• ISSN: 0014-827X; 1879-0569
• DOI: 10.1016/S0014-827X(01)01146-6

This paper reports the synthesis of a series of new 5-substituted-1-(2-hydroxybenzoyl)-benzotriazoles, which have been tested for their activity as possible activators of potassium channels. In rat aortic rings, the ‘opened’ derivatives
1a–
f, intermediates of synthesis, showed vasorelaxing properties, with appreciable values of potency. However, the most remarkable effects were recorded for the 2-hydroxybenzoylbenzotriazoles
3a–
f, which showed full vasorelaxing efficacy and high potency values. The introduction of a 2-hydroxybenzyl substituent in the 1 position of the benzotriazole ring (compound
7) strongly decreased the activity, showing the importance of the electron-acceptor carbonyl function. The best compound,
3b, was further investigated, in order to evaluate the possible mechanism of action involved in the vasodilator activity. In the vascular model, different potassium channel blockers inhibited the effects of the compound, and an increase of the levels of membrane depolarisation induced a significant reduction of the recorded responses. Compound
3b was also tested in a model of isolated rat heart, retroperfused through the aorta and submitted to a global ischemia/reperfusion cycle. In such an experimental condition,
3b showed an interesting cardioprotective activity. All the above observations are in agreement with the hypothesis of a mechanism linked to the activation of potassium channels.