Evaluation and lead optimization of anti-malarial acridones. Export

@article{citeulike:808568, abstract = {With 2-methoxy-6-chloroacridone as a lead compound, we synthesized and tested acridone derivatives to develop a better understanding of the anti-malarial structure-activity relationships. Over 30 acridone derivatives were synthesized. The most potent compounds contained extended alkyl chains terminated by trifluoromethyl groups and located at the 3-position of the tricyclic system. Acridones optimized in the length of the side chain and the nature of the terminal fluorinated moiety exhibited in vitro anti-malarial IC(50) values in the low nanomolar and picomolar range and were without cytotoxic effects on the proliferation and differentiation of human bone marrow progenitors or mitogen-activated murine lymphocytes at concentrations up to 100,000-fold higher. Based on a structural similarity to known anti-malarial agents it is proposed that the haloalkoxyacridones exert their anti-malarial effects through inhibition of the Plasmodium cytochrome bc(1) complex. Haloalkoxyacridones represent an extraordinarily potent novel class of chemical compounds with the potential for development as therapeutic agents to treat or prevent malaria in humans.}, address = {Medical Research Service, RD-33, VA Medical Center, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, USA; Department of Chemistry, Portland State University, Portland, OR 97207, USA.}, author = {Winter, R. W. and Kelly, J. X. and Smilkstein, M. J. and Dodean, R. and Bagby, G. C. and Rathbun, R. K. and Levin, J. I. and Hinrichs, D. and Riscoe, M. K.}, citeulike-article-id = {808568}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.exppara.2006.03.014}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16828746}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16828746}, comment = {On 23 November 2006 my evaluation of this article was published by "Faculty of 1000 Medicine", see the following link: http://www.f1000medicine.com/article/id/1047623/evaluation}, doi = {10.1016/j.exppara.2006.03.014}, issn = {0014-4894}, journal = {Exp Parasitol}, keywords = {acridone, acridones, anti-malarial, antimalarial, f1000medicine, falciparum, lead\_optimization, malaria, plasmodium}, month = {September}, number = {1}, pages = {47--56}, posted-at = {2006-08-20 01:57:26}, priority = {2}, title = {Evaluation and lead optimization of anti-malarial acridones.}, url = {http://dx.doi.org/10.1016/j.exppara.2006.03.014}, volume = {114}, year = {2006} }

TY - JOUR ID - citeulike:808568 L3 - citeulike-article-id:808568 N2 - With 2-methoxy-6-chloroacridone as a lead compound, we synthesized and tested acridone derivatives to develop a better understanding of the anti-malarial structure-activity relationships. Over 30 acridone derivatives were synthesized. The most potent compounds contained extended alkyl chains terminated by trifluoromethyl groups and located at the 3-position of the tricyclic system. Acridones optimized in the length of the side chain and the nature of the terminal fluorinated moiety exhibited in vitro anti-malarial IC(50) values in the low nanomolar and picomolar range and were without cytotoxic effects on the proliferation and differentiation of human bone marrow progenitors or mitogen-activated murine lymphocytes at concentrations up to 100,000-fold higher. Based on a structural similarity to known anti-malarial agents it is proposed that the haloalkoxyacridones exert their anti-malarial effects through inhibition of the Plasmodium cytochrome bc(1) complex. Haloalkoxyacridones represent an extraordinarily potent novel class of chemical compounds with the potential for development as therapeutic agents to treat or prevent malaria in humans. IS - 1 JF - Exp Parasitol SN - 0014-4894 AD - Medical Research Service, RD-33, VA Medical Center, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, USA; Department of Chemistry, Portland State University, Portland, OR 97207, USA. EP - 56 TI - Evaluation and lead optimization of anti-malarial acridones. VL - 114 SP - 47 KW - acridone KW - acridones KW - anti-malarial KW - antimalarial KW - f1000medicine KW - falciparum KW - lead_optimization KW - malaria KW - plasmodium N1 - On 23 November 2006 my evaluation of this article was published by "Faculty of 1000 Medicine", see the following link: http://www.f1000medicine.com/article/id/1047623/evaluation AU - Winter, RW AU - Kelly, JX AU - Smilkstein, MJ AU - Dodean, R AU - Bagby, GC AU - Rathbun, RK AU - Levin, JI AU - Hinrichs, D AU - Riscoe, MK PY - 2006/09// UR - http://dx.doi.org/10.1016/j.exppara.2006.03.014 ER -