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dc.contributor.authorWang, Michael Zhuo
dc.contributor.authorZhu, Xiaohua
dc.contributor.authorSrivastava, Anuradha
dc.contributor.authorLiu, Qiang
dc.contributor.authorSweat, J. Mark
dc.contributor.authorPandharkar, Trupti
dc.contributor.authorStephens, Chad E.
dc.contributor.authorRicco, Ed
dc.contributor.authorParman, Toufan
dc.contributor.authorMunde, Manoj
dc.contributor.authorMadal, Swati
dc.contributor.authorMadhubala, Rentala
dc.contributor.authorTidwell, Richard R.
dc.contributor.authorWilson, W. David
dc.contributor.authorBoykin, David W.
dc.contributor.authorHall, James E.
dc.contributor.authorKyle, Dennis E.
dc.contributor.authorWerbovetz, Karl A.
dc.identifier.citationWang et al. "Novel Arylimidamides for Treatment of Visceral Leishmaniasis." Antimicrob. Agents Chemother. June 2010 vol. 54 no. 6 2507-2516.
dc.description.abstractArylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC50], <1 μM) 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 (IC50 ≤ 0.12 μM) 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.en_US
dc.publisherThe American Society for Microbiologyen_US
dc.titleNovel Arylimidamides for Treatment of Visceral Leishmaniasisen_US
kusw.kuauthorWang, Michael Zhou
kusw.kudepartmentDepartment of Pharmaceutical Chemistryen_US
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.

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