Triazolines. 14. 1,2,3-Triazolines and triazoles. A new class of anticonvulsants. Drug design and structure-activity relationships

Abstract

Pioneering studies in our laboratories have led to the emergence of the delta 2-1,2,3-triazolines (4,5-dihydro-1H-1,2,3-triazoles) and the closely related 1H-1,2,3-triazoles as a unique family of anticonvulsant agents hitherto unknown. Unlike the traditional anticonvulsants, the dicarboximide moiety is absent from the traiazoline ring system. This paper examines the results of evaluation of several groups of 1-aryl-5-pyridyl-substituted triazolines and triazoles with particular reference to structure-activity relationships in each compound group as well as between compounds in the different groups and the 1,5-diaryl compounds. The Topliss manual approach for application fo the Hansch method is employed for the rational design of triazoline/triazole anticonvulsants. Anticonvulsant activity was determined, after intraperitoneal administration, in two standard seizure models in the mouse, the MES and scMet tests. Central nervous system toxicity was evaluated in the rotorod ataxia test. Analysis of structure-activity relationships using the Topliss scheme indicated a clear pi + sigma dependency in the 1-aryl-5-(4-pyridyl)triazolines while an adverse steric effect (Es) from 4-substitution appeared to be present in the 1-aryl-5-(3-pyridyl) compounds. A similar but strong steric effect dominated the structure-activity pattern of the 1-aryl-5-(4-pyridyl)triazoles, although a sigma dependency was more evident in the 1-aryl-5-(3-pyridyl)- and the 1,5-diaryltriazole series. No significant activity was observed among the 1-aryl-5-(2-pyridyl)triazolines, and although the respective triazoles were active, the parameter dependency was not clearly defined. Similarly, the 1,5-diaryltriazolines, as a group, showed no pronounced anticonvulsant activity. However, replacement of the 5-aryl with a pyridyl group, particularly a 4-pyridyl, led to highly enhanced anticonvulsant activity. In addition, oxidation of triazolines with no anticonvulsant activity yielded, as a rule, triazoles that were active, which could be linked to their chemistry or structural conformation. The triazolines and triazoles evince anticonvulsant activity as a class and compare very well with the prototype antiepileptic drugs--ethosuximide, phenytoin, phenobarbital, valproate--in their anticonvulsant potency and minimal neurotoxicity. They have emerged as a new generation of anticonvulsant agents that show great promise as potentially useful antiepileptic drugs.

Studies with 2-arylhydrazononitriles: a new convenient synthesis of 2, 4-disubstituted- 1,2,3-triazole-5-amines

“…1,2,3-triazoles constitute a class of compounds which have attracted considerable attention in industry, agricultural and medicinal chemistry [1][2][3][4] . Owing to their importance an impressive number of work has been published on the chemistry and synthesis of 1,2,3-triazoles [5][6][7][8][9][10][11][12][13][14][15][16] .…”

Rational Drug Design and the Discovery of the Δ2-1,2,3-Triazolines, A Unique Class of Anticonvulsant and Antiischemic Agents

“…It may be considered as a "built-in" "heterocyclic prodrug"; the dicarboximide moiety (-CO-NH-CO-), which is an integral part of the traditional anticonvulsant drugs, (Fig. 1), is absent in the triazolines [18]. While the nonaromatic triazoline ring system [12] may behave like aliphatic azo compounds, the additional basic ring nitrogen N-1 could give rise to reaction paths not encountered in simpler systems.…”

“…Evaluation of Hanschtype structure -activity relationships in several different groups of 1, 5-disubstituted (I-III) and 1, 4, 5-trisubstituted (IV) 1,2,3-triazolines has indicated that while the 1,5-diaryltriazolines (IA) as a group, show no pronounced anticonvulsant action [17], replacement of the 5-aryl with a heterocyclic substituent, particularly a 4-pyridyl (II) [18] or a 2-oxo-1-pyrrolidinyl (III) [19], leads to highly enhanced anticonvulsant activity (Fig. 2).…”

The determination of the stability constants of complexes of 1,2,4-triazoles and biologically relevant ligands with M(II) by potentiometric titration in aqueous solution

“…Complexes of triazoles play a significant role in biological processes [12][13][14][15], such as anti-inflammatory, antimycobacterials [16], and anticonvulsants [17]. Metal complexes of triazoles are used to produce pharmaceutical compounds to inhibit tumor growth and cancer in mammals [18][19][20][21]. Such compounds are also used to treat viral as well as bacterial infections [22][23][24].…”