Chemotherapie der experimentellen Tuberkulose IV. Aminosäure‐Derivate des Isonicotinsäurehydrazids und des 2‐Methyl‐isonicotinsäurehydrazids

Abstract

Some 27 N‐acyl derivatives of isonicotinic acid hydrazide and 2‐methylisonicotinic acid hydrazide with amino acids and acylamino acids have been synthesized. The synthesis of the acylamino acyl compounds was carried out according to three different methods:(1) condensation of an acylated amino acid hydrazide with isonicotinic acid chloride hydrochloride or 2‐methylisonicotinic acid chloride hydrochloride, resp.,(2) condensation of an acylated amino acid chloride with isonicotinic acid hydrazide or 2‐methylisonicotinic acid hydrazide, resp., and(3) condensation of an acylated amino acid thiol ester with isonicotinic acid hydrazide.The synthesis of the amino acid compounds with a free amino group was carried out in all cases by condensation of a carbobenzoxy amino acid with isonicotinic acid hydrazide according to the peptide synthesis of Boissonnas‐Wieland with subsequent hydrogenolysis of the carbobenzoxy group. These substances have been isolated either as free bases or as the respective chlorohydrates.Biological tests revealed that, as a rule, derivatives of α‐amino acids possess an activity comparable to that of unsubstituted isonicotinic acid hydrazide or 2‐methylisonicotinic acid hydrazide, resp., derivatives of β‐ and γ‐amino acids being almost inactive. All the derivatives exhibit lower acute toxicity than isoniazide. Some of them are practically non‐toxic. The optical configuration of the amino acids frequently has a pronounced influence on the activity of the condensation products.