9-Anilinoacridines as potential antileishmanial agents

Abstract

A number of 1'-substituted 9-anilinoacridines were evaluated for their activities against promastigote and amastigote forms of Leishmania major and for their toxicities to human Jurkat leukemia cells. Several compounds possessing l'-NH-alkyl substituents produced more than 80% growth inhibition of macrophageinfected L. major amastigotes at or below a concentration of 1 ,uM. l'-Hexylamino-9-anilinoacridine (compound 14) was the least toxic compound to human Jurkat cells, while it retained strong antileishmanial activity. There was a general trend for the more lipophilic compounds to show the greatest antileishmanial activity, whereas 3,6-di-NH2 substitution of the acridine nucleus reduced or eliminated activity. Some structure-activity relationships of the various compounds are discussed.The widespread occurrence of leishmaniasis (2) and the limited repertoire of drugs currently capable of treating leishmanial infections without undesirable side effects (18) are spurring efforts to find more effective cures for the disease. There is evidence that some drugs active against bacterial and mammalian DNA topoisomerases II have limited activity against Leishmania donovani (7) and Leishmania mexicana (20) and that two other potent antileishmanial drugs, sodium stibogluconate and ureastilbamine, inhibit DNA topoisomerase I of L. donovani (6). Also, it was recently reported that a number of aminoacridines have in vitro activity against Leishmania promastigotes (21). These observations suggested that a more systematic study of DNA topoisomerase inhibitors for their potential activities against trypanosomes, and in particular Leishmania species, would be worthwhile.Anilinoacridines have successfully been used to target isozymes of mammalian DNA topoisomerase II (3,14), and various analogs are clinically effective against some forms of cancer (11,12). Therefore, we tested a wide variety of substituted 9-anilinoacridines for their activities against Trypanosoma lewisi (9) and, on the assumption that protozoal DNA topoisomerases would be closely related, the subset of compounds most active against T. lewisi and additional derivatives were screened against L. major. In the present study we identified a small group of compounds that show in vitro activity against macrophage-infected L. major in the concentration range of <0.1 to 1 ,uM. The structures and properties of the range of compounds tested together with data on their activities against L. major and their toxicities to human Jurkat cells are described. The results confirm that it is possible to modify existing anticancer drugs targeted at DNA topoisomerase II and improve their activities and specificities against other organisms, such as trypanosomes, that cause leishmaniasis. Better knowledge of the structure-activity relationships that increase the potencies of drugs against parasite DNA topoisomerases and that decrease their activities against human cells is now being sought to aid in the design of new drugs that are effective against these and other pathogenic parasi...

One‐pot Synthesis of 14‐Aryl‐1,6,7,14‐tetrahydrodibenzo‐[a,i]acridine‐1,6‐dione in Ionic Liquid

“…Among them, acridine and its derivatives containing a 1,4-dihydropyridine moiety are under constant investigation in view of their profound range of biological activities such as antitumor, 2 antibacterial, 3 antimalarial 4 and antinociceptive activities. 5 The 1,4-naphthoquinone structure is common in numerous natural products associated with antifungal, 6 antibacterial 7 and antiviral activities.…”

SnO2 nanoparticles mediated nontraditional synthesis of biologically active 9-chloro-6,13-dihydro-7-phenyl-5H-indolo [3,2-c]-acridine derivatives

“…It can be concluded that there is urgent need to search new anticancer agents (Da et al, 1994). Acridine derivatives are one of the more studied chemotherapeutic compounds, widely used as antimalarial, antiprotozoal (Gamage et al, 1997), antibacterial (Mauel et al, 1993), and antitumor agents (Sugaya et al, 1994). Many modifications have been made to the acridine skeleton in the search for anticancer compounds.…”

In Vitro Action of ent-Manoyl Oxides against Leishmania donovani

“…The NMR spectra (300 MHz for 1 H and 75.4 MHz for 13 C) were determined in CDCl 3 solution (which also provided the lock signal) on a Bruker AM-300 spectrometer. Assignments of 13 C-NMR chemical shifts were made with the aid of distortionless enhancement by polarization transfer (DEPT) using a flip angle of 135°. IR spectra were run on a Perkin-Elmer 983 G spectrometer.…”

“…Some imidazole, oxazole, and thiazole derivatives are effective against leishmaniasis. 10,11 Carbazolylpyrimidine, 12 9-anilinoacridin, 13 acridinobenzimidazole compounds, 14 and a naturally occurring labdane diterpenoid 15 are also promising antileishmanial agents. A series of organometalic complexes of Pt(II), Pt(IV), Rh(I), Rh(III), Rh(IV), and Sb(III) have also shown antileishmanical activity in vitro.…”