TY - JOUR
T1 - Identification of benzoylisoquinolines as potential anti-Chagas agents
AU - Byler, Kendall G.
AU - Brito-Arias, Marco
AU - Marquez-Navarro, Adrian
AU - Nogueda-Torres, Benjamin
AU - Torres-Bustillos, Luis G.
AU - Martínez-Mayorga, Karina
N1 - Funding Information:
MBA is grateful to SIP and COFAA IPN for financial support. KMM thanks the State of Florida, Executive Officer of the Governor’s Office of Tourism, Trade and Economic Development for funding. Authors thank OpenEye Scientific Software for providing the OMEGA, ROCS and VIDA programs.
PY - 2012/4/15
Y1 - 2012/4/15
N2 - A set of three 3-benzoyl substituted isoquinolones was synthesized in good yields and assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease. Depending on the concentration evaluated, a greater or equivalent reduction in the number of bloodborne trypomastigotes compared to that observed with benznidazole, a drug currently used to attack the parasite, was observed for two of the samples. In order to assess the potential of the 3-benzoylisoquinolone nucleus as a possible scaffold in the design of novel anti-trypanosomal lead structures, a computational analysis was performed using structural and inhibition information from both functional and target assays archived in the online database, ChEMBL. Chemical space projection of the synthesized compounds along with 3067 structures with known activities against T. cruzi shows that the isoquinolones occupy a sparsely-populated region of chemical space, indicating their potential for development as a novel class of trypanocidals. In addition, 2D and 3D structural similarity analyses revealed micromolar and submicromolar inhibitors of T. cruzi in ChEMBL with high similarity to the synthesized structures.
AB - A set of three 3-benzoyl substituted isoquinolones was synthesized in good yields and assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease. Depending on the concentration evaluated, a greater or equivalent reduction in the number of bloodborne trypomastigotes compared to that observed with benznidazole, a drug currently used to attack the parasite, was observed for two of the samples. In order to assess the potential of the 3-benzoylisoquinolone nucleus as a possible scaffold in the design of novel anti-trypanosomal lead structures, a computational analysis was performed using structural and inhibition information from both functional and target assays archived in the online database, ChEMBL. Chemical space projection of the synthesized compounds along with 3067 structures with known activities against T. cruzi shows that the isoquinolones occupy a sparsely-populated region of chemical space, indicating their potential for development as a novel class of trypanocidals. In addition, 2D and 3D structural similarity analyses revealed micromolar and submicromolar inhibitors of T. cruzi in ChEMBL with high similarity to the synthesized structures.
KW - Benzoyl isoquinolones
KW - Chemical space
KW - Structural similarity
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=84859423617&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2012.02.046
DO - 10.1016/j.bmc.2012.02.046
M3 - Artículo
C2 - 22436391
SN - 0968-0896
VL - 20
SP - 2587
EP - 2594
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 8
ER -