Novel arylimidamides for treatment of visceral leishmaniasis

Michael Zhuo Wang, Xiaohua Zhu, Anuradha Srivastava, Qiang Liu, J. Mark Sweat, Trupti Pandharkar, Chad E. Stephens, Ed Riccio, Toufan Parman, Manoj Munde, Swati Mandal, Rentala Madhubala, Richard R. Tidwell, W. David Wilson, David W. Boykin, James Edwin Hall, Dennis E. Kyle, Karl A. Werbovetz

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Arylimidamides (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.

Original languageEnglish (US)
Pages (from-to)2507-2516
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number6
DOIs
StatePublished - Jun 1 2010

Fingerprint

Visceral Leishmaniasis
Leishmania donovani
Parasitemia
Cricetinae
Inhibitory Concentration 50
Liver
Spleen
Pharmacokinetics
Leishmania major
Leishmania
Eosinophilia
Hypertrophy
Biological Availability
Half-Life
Hepatocytes
Bone Marrow
Body Weight
Kidney
Serum

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Wang, M. Z., Zhu, X., Srivastava, A., Liu, Q., Sweat, J. M., Pandharkar, T., ... Werbovetz, K. A. (2010). Novel arylimidamides for treatment of visceral leishmaniasis. Antimicrobial Agents and Chemotherapy, 54(6), 2507-2516. https://doi.org/10.1128/AAC.00250-10

Novel arylimidamides for treatment of visceral leishmaniasis. / Wang, Michael Zhuo; Zhu, Xiaohua; Srivastava, Anuradha; Liu, Qiang; Sweat, J. Mark; Pandharkar, Trupti; Stephens, Chad E.; Riccio, Ed; Parman, Toufan; Munde, Manoj; Mandal, Swati; Madhubala, Rentala; Tidwell, Richard R.; Wilson, W. David; Boykin, David W.; Hall, James Edwin; Kyle, Dennis E.; Werbovetz, Karl A.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 6, 01.06.2010, p. 2507-2516.

Research output: Contribution to journalArticle

Wang, MZ, Zhu, X, Srivastava, A, Liu, Q, Sweat, JM, Pandharkar, T, Stephens, CE, Riccio, E, Parman, T, Munde, M, Mandal, S, Madhubala, R, Tidwell, RR, Wilson, WD, Boykin, DW, Hall, JE, Kyle, DE & Werbovetz, KA 2010, 'Novel arylimidamides for treatment of visceral leishmaniasis', Antimicrobial Agents and Chemotherapy, vol. 54, no. 6, pp. 2507-2516. https://doi.org/10.1128/AAC.00250-10
Wang MZ, Zhu X, Srivastava A, Liu Q, Sweat JM, Pandharkar T et al. Novel arylimidamides for treatment of visceral leishmaniasis. Antimicrobial Agents and Chemotherapy. 2010 Jun 1;54(6):2507-2516. https://doi.org/10.1128/AAC.00250-10
Wang, Michael Zhuo ; Zhu, Xiaohua ; Srivastava, Anuradha ; Liu, Qiang ; Sweat, J. Mark ; Pandharkar, Trupti ; Stephens, Chad E. ; Riccio, Ed ; Parman, Toufan ; Munde, Manoj ; Mandal, Swati ; Madhubala, Rentala ; Tidwell, Richard R. ; Wilson, W. David ; Boykin, David W. ; Hall, James Edwin ; Kyle, Dennis E. ; Werbovetz, Karl A. / Novel arylimidamides for treatment of visceral leishmaniasis. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 6. pp. 2507-2516.
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