Collect. Czech. Chem. Commun. 1999, 64, 1902-1924
https://doi.org/10.1135/cccc19991902

Relationships Between the Chemical Structure of Substances and Their Antimycobacterial Activity Against Atypical Strains. Part 18. 3-Phenyl-2H-1,3-benzoxazine-2,4(3H)-diones and Isosteric 3-Phenylquinazoline-2,4(1H,3H)-diones

Karel Waissera,*, Miloš Macháčeka, Hynek Dostála, Jiří Gregora, Lenka Kubicováa, Věra Klimešováa, Jiří Kuneša,b, Karel Palát, Jr.a, Jana Hladůvkováa, Jarmila Kaustovác and Ute Möllmannd

a Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic
b Laboratory of Structure and Interactions of Biologically Active Molecules, Faculty of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic
c National Reference Laboratory for Mycobacterium kansasii, Regional Institute of Hygiene, 728 92 Ostrava, Czech Republic
d Hans Knöll Institute of Natural Products Research, 07745 Jena, Germany

Abstract

A series of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones 2 and 3-phenylquinazoline-2,4(1H,3H)-diones 5 substituted on the phenyl rings were synthesized. The target compounds as well as the intermediates were tested against Mycobacterium tuberculosis, M. kansasii, and M. avium. The replacement of the oxygen atom by nitrogen resulted in a decrease or loss of antimycobacterial activity. 2-[(Ethoxycarbonyl)amino]benzanilides 4 appeared to be inactive. Salicylanilides 1 and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones 2 exhibit significant activity against both M. tuberculosis and nontuberculous mycobacteria (the MICs within the range of 4-250 μmol/l for all compounds). The antimycobacterial activity of the compounds increases with increasing both electron-withdrawing properties and hydrophobicity of the substituent(s) on the phenyl moiety. The antimycobacterial profile of the compounds was analyzed according to the criteria based on vector algebra, such as cosine coefficients. Moreover, salicylanilides 1 exhibit activity against other microorganisms tested by the agar diffusion method.

Keywords: Tuberculostatics; Antimicrobial activity; QSAR; 1,3-Benzoxazines; Quinazolines; Salicylanilides; Anthranilanilides; Cosine coefficient.