Search for biologically active compounds in the series of indazole derivatives

Abstract

Indazole compounds are intensively used in the synthesis of new active substances for pharmacological purposes. The present work includes methods of modification and preparation of new indazole compounds, determination of their biological activity (antibacterial properties, antiprotozoal and fungistatic activity). Modification methods were used: the recyclization reaction; acetylation of the amino group; acylation and others. We have synthesized indazole derivatives containing an aryl substituent with a 2-aminoethyl fragment by recyclization of 1-(2-chloroaryl)-3,4-dihydroioquinolines under the influence of hydrazine. The starting structures for the synthesis of indazoles (compounds 5, 6, 7) possess negligible activity toward Colpoda steinii, are practically inactive toward Penicillium italicum but retard the growth of E. coli and Staphylococcus aureus (retard zone 7-9 mm); compounds with dimethoxy groups in the benzene ring (compounds 5 and 6) are active toward E. coli whereas structure 7 has no activity without dimethoxy groups. The recycling reaction leading to indazole structures considerably increases the activity of all compounds (1-4, 8-14). Compounds with a primary amino group (structures 1, 2, and 9) possess marked antiprotozoan activity, the best results in this respect being demonstrated by compound 9 which does not contain dimethoxy groups in the benzene ring (15.6 ?g/ml). Acylation of the amino group in compound 2 allows a 4-fold increase in antiprotozoic activity and a slight fungistatic activity (compound 3). At the same time, acylation with a bulkier and more lipophilic benzoyl group (compound 4) practically suppresses antiprotozoic and fungistatic activities. It should be noted that conversion of the primary amino group of compounds 1 and 9 to the tertiary amino group (compounds 13 and 14) allows a dramatic increase in antiprotozoal activity (31.25 µg/ml for compound 1 and 3.9 µg/ml for compound 13; 15.6 µg/ml for compound 9 and 3.9 µg/ml for compound 14). In addition, these same compounds 13 and 14, unlike compounds 1 and 9, are active against all cultures studied. The best results are shown by compounds 11 and 12 in which the amino group is part of the urea structure.