Synthesis and evaluation of novel 7-trifluoromethyl-4-(4-substituted anilino)quinolines as antiparasitic and antineoplastic agents.
Several novel derivatives bearing the 7-trifluoromethyl-4-(4-substituted anilino)-quinoline skeleton were synthesized and evaluated for their in vitro activity against the blood streaming form of the parasites Trypanosoma brucei rhodesiense, the trypomastigotes of Trypanosoma cruzi cultured in rat skeletal myoblasts, the amastigotes form of Leishmania donovani, Plasmodium falciparum (K1 strain) infected erythrocyte suspension, as well as their toxicity towards rat skeletal L-6 cells. In addition, three of the synthesized compounds were tested for their in vitro antitumor activity towards 60 human tumor cell lines by the National Cancer Institute (NCI). Compound 1-(4-[[7-(trifluoromethyl)quinolin-4-yl]amino]phenyl)ethan-1-one thiosemicarbazone 23 exhibited potential activity against T. b. rhodesiense, T. cruzi and P. falciparum with IC50's of 0.278, 0.85 and 0.417 microgram/ml, respectively. These values are even more valuable since this compound was clearly non-toxic (cytotoxicity IC50 > 90 micrograms/ml), leading to in vitro therapeutic indices of > 323, > 106 and > 216, respectively. Meanwhile, compound N-[4-[5-(4-chlorophenyl)-4,5-dihydroisoxazol-3-yl]phenyl]-7-(trifluoromethyl) quinolin-4-amine 21 showed broad spectrum antitumor activity with full panel median growth inhibition GI50 (MG-MID) of 1.95 mumol and total growth inhibition TGI (MG-MID) of 6.87 mumol, respectively. Compound 23 represents a very good prospective as a lead compound able to combat three tropical diseases at a time. However, the pattern for the antitumor activity did not parallel any of the antiparasitic ones, indicating that non-common mechanisms of action may exist among these activities.
Abadi
Ashraf H
AH
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt. ahabadi@yahoo.com
Brun
Reto
R
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000977:Antiparasitic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007202:Indicators and Reagents; D007893:Leishmania donovani / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D000977:Antiparasitic Agents; D007202:Indicators and Reagents; D011804:Quinolines