TY - JOUR
T1 - Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection
AU - da Silva, Cristiane França
AU - Batista, Denise da Gama Jaén
AU - de Araújo, Julianna Siciliano
AU - Cunha-Junior, Edézio Ferreira
AU - Stephens, Chad E.
AU - Banerjee, Moloy
AU - Farahat, Abdelbasset A.
AU - Akay, Senol
AU - Fisher, Mary K.
AU - Boykin, David W.
AU - Soeiro, Maria de Nazaré Correia
N1 - Funding Information:
This work was supported by Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ; E-26/102.839/2011; 203636 and 200381), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 555010/2008-2, 301372/2015-2), Fundação Oswaldo Cruz, Program for Technological Development in Tools for Health, PAEF/CNPq/Fiocruz, and CAPES (23038.009424/2012-50, 23038008979201/10-1). MDNCS is a research fellow of CNPq and CNE research. The authors thank the Program for Technological Development in Tools for Health-PDTIS-Fiocruz for use of its facilities. The present study was supported by grants from, in part by, the Bill & Melinda Gates Foundation through a subcontract with the Consortium for Parasitic Drug Development (to DWB – R01AI64200). The authors also thank Marcos Meuser Batista for his assistance in their experiments and Eduardo Caio Torres-Santos for his assistance in ADMET in silico analysis.
Publisher Copyright:
© 2017 da Silva et al.
PY - 2017/4/3
Y1 - 2017/4/3
N2 - Arylimidamides (AIAs), previously termed as reversed amidines, present a broad spectrum of activity against intracellular microorganisms. In the present study, three novel AIAs were evaluated in a mouse model of Trypanosoma cruzi infection, which is the causative agent of Chagas disease. The bis-AIAs DB1957, DB1959 and DB1890 were chosen based on a previous screening of their scaffolds that revealed a very promising trypanocidal effect at nanomolar range against both the bloodstream trypomastigotes (BTs) and the intracellular forms of the parasite. This study focused on both mesylate salts DB1957 and DB1959 besides the hydrochloride salt DB1890. Our current data validate the high activity of these bis-AIA scaffolds that exhibited EC50 (drug concentration that reduces 50% of the number of the treated parasites) values ranging from 14 to 78 nM and 190 to 1,090 nM against bloodstream and intracellular forms, respectively, also presenting reasonable selectivity indexes and no mutagenicity profile predicted by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET). Acute toxicity studies using murine models revealed that these AIAs presented only mild toxic effects such as reversible abdominal contractions and ruffled fur. Efficacy assays performed with Swiss mice infected with the Y strain revealed that the administration of DB1957 for 5 consecutive days, with the first dose given at parasitemia onset, reduced the number of BTs at the peak, ranging between 21 and 31% of decrease. DB1957 was able to provide 100% of animal survival, while untreated animals showed 70% of mortality rates. DB1959 and DB1890B did not reduce circulating parasitism but yielded >80% of survival rates.
AB - Arylimidamides (AIAs), previously termed as reversed amidines, present a broad spectrum of activity against intracellular microorganisms. In the present study, three novel AIAs were evaluated in a mouse model of Trypanosoma cruzi infection, which is the causative agent of Chagas disease. The bis-AIAs DB1957, DB1959 and DB1890 were chosen based on a previous screening of their scaffolds that revealed a very promising trypanocidal effect at nanomolar range against both the bloodstream trypomastigotes (BTs) and the intracellular forms of the parasite. This study focused on both mesylate salts DB1957 and DB1959 besides the hydrochloride salt DB1890. Our current data validate the high activity of these bis-AIA scaffolds that exhibited EC50 (drug concentration that reduces 50% of the number of the treated parasites) values ranging from 14 to 78 nM and 190 to 1,090 nM against bloodstream and intracellular forms, respectively, also presenting reasonable selectivity indexes and no mutagenicity profile predicted by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET). Acute toxicity studies using murine models revealed that these AIAs presented only mild toxic effects such as reversible abdominal contractions and ruffled fur. Efficacy assays performed with Swiss mice infected with the Y strain revealed that the administration of DB1957 for 5 consecutive days, with the first dose given at parasitemia onset, reduced the number of BTs at the peak, ranging between 21 and 31% of decrease. DB1957 was able to provide 100% of animal survival, while untreated animals showed 70% of mortality rates. DB1959 and DB1890B did not reduce circulating parasitism but yielded >80% of survival rates.
KW - Arylimidamides
KW - Chagas disease
KW - Experimental chemotherapy
KW - In vivo assays
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U2 - 10.2147/DDDT.S120618
DO - 10.2147/DDDT.S120618
M3 - Article
C2 - 28435221
AN - SCOPUS:85017210271
SN - 1177-8881
VL - 11
SP - 1095
EP - 1105
JO - Drug Design, Development and Therapy
JF - Drug Design, Development and Therapy
ER -