Novel arylimidamides for treatment of visceral leishmaniasis.
Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC(50) < or = 0.12 microM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL.
Wang
Michael Zhuo
MZ
Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. michael.wang@unc.edu
Zhu
Xiaohua
X
Srivastava
Anuradha
A
Liu
Qiang
Q
Sweat
J Mark
JM
Pandharkar
Trupti
T
Stephens
Chad E
CE
Riccio
Ed
E
Parman
Toufan
T
Munde
Manoj
M
Mandal
Swati
S
Madhubala
Rentala
R
Tidwell
Richard R
RR
Wilson
W David
WD
Boykin
David W
DW
Hall
James Edwin
JE
Kyle
Dennis E
DE
Werbovetz
Karl A
KA
D000578:Amidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000981:Antiprotozoal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001682:Biological Availability; D006224:Cricetinae; D004195:Disease Models, Animal; D055808:Drug Discovery; D005260:Female; D005663:Furans / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007893:Leishmania donovani / Q000187:drug effects; D018320:Leishmania major / Q000187:drug effects; D007894:Leishmania mexicana / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000378:metabolism / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D018512:Parasitemia / Q000188:drug therapy; D021261:Parasitic Sensitivity Tests; D013154:Spleen / Q000469:parasitology; D014018:Tissue Distribution
C552046:2,5-bis(2-(2-propoxy)-4-(2-pyridylimino)aminophenyl)furan; C552045:2,5-bis(2-ethoxy-4-(2-pyridylimino)aminophenyl)furan; D000578:Amidines; D000981:Antiprotozoal Agents; D005663:Furans