Evaluation of arylimidamides DB1955 and DB1960 as candidates against visceral leishmaniasis and Chagas' disease: In vivo efficacy, acute toxicity, pharmacokinetics, and toxicology studies

Xiaohua Zhu, Qiang Liu, Sihyung Yang, Toufan Parman, Carol E. Green, Jon C. Mirsalis, Maria De Nazaré Correia Soeiro, Elen Mello De Souza, Cristiane França Da Silva, Denise Da Gama Jaen Batista, Chad E. Stephens, Moloy Banerjee, Abdelbasset A. Farahat, Manoj Munde, W. David Wilson, David W. Boykin, Michael Zhuo Wang, Karl A. Werbovetz

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Arylimidamides (AIAs) have shown outstanding in vitro potency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2- pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good in vivo efficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility and in vivo antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day X 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murine Trypanosoma cruzi infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day X 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.

Original languageEnglish (US)
Pages (from-to)3690-3699
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume56
Issue number7
DOIs
StatePublished - Jul 1 2012

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Visceral Leishmaniasis
Parasitemia
Chagas Disease
Toxicology
Pharmacokinetics
Mesylates
Liver
Salts
Kidney
Tachypnea
Trypanosoma cruzi
Blood Urea Nitrogen
Tremor
Aspartate Aminotransferases
Serum
Alanine Transaminase
Posture
L-Lactate Dehydrogenase
Solubility
Rodentia

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Evaluation of arylimidamides DB1955 and DB1960 as candidates against visceral leishmaniasis and Chagas' disease : In vivo efficacy, acute toxicity, pharmacokinetics, and toxicology studies. / Zhu, Xiaohua; Liu, Qiang; Yang, Sihyung; Parman, Toufan; Green, Carol E.; Mirsalis, Jon C.; Soeiro, Maria De Nazaré Correia; De Souza, Elen Mello; Da Silva, Cristiane França; Batista, Denise Da Gama Jaen; Stephens, Chad E.; Banerjee, Moloy; Farahat, Abdelbasset A.; Munde, Manoj; Wilson, W. David; Boykin, David W.; Wang, Michael Zhuo; Werbovetz, Karl A.

In: Antimicrobial Agents and Chemotherapy, Vol. 56, No. 7, 01.07.2012, p. 3690-3699.

Research output: Contribution to journalArticle

Zhu, X, Liu, Q, Yang, S, Parman, T, Green, CE, Mirsalis, JC, Soeiro, MDNC, De Souza, EM, Da Silva, CF, Batista, DDGJ, Stephens, CE, Banerjee, M, Farahat, AA, Munde, M, Wilson, WD, Boykin, DW, Wang, MZ & Werbovetz, KA 2012, 'Evaluation of arylimidamides DB1955 and DB1960 as candidates against visceral leishmaniasis and Chagas' disease: In vivo efficacy, acute toxicity, pharmacokinetics, and toxicology studies', Antimicrobial Agents and Chemotherapy, vol. 56, no. 7, pp. 3690-3699. https://doi.org/10.1128/AAC.06404-11
Zhu, Xiaohua ; Liu, Qiang ; Yang, Sihyung ; Parman, Toufan ; Green, Carol E. ; Mirsalis, Jon C. ; Soeiro, Maria De Nazaré Correia ; De Souza, Elen Mello ; Da Silva, Cristiane França ; Batista, Denise Da Gama Jaen ; Stephens, Chad E. ; Banerjee, Moloy ; Farahat, Abdelbasset A. ; Munde, Manoj ; Wilson, W. David ; Boykin, David W. ; Wang, Michael Zhuo ; Werbovetz, Karl A. / Evaluation of arylimidamides DB1955 and DB1960 as candidates against visceral leishmaniasis and Chagas' disease : In vivo efficacy, acute toxicity, pharmacokinetics, and toxicology studies. In: Antimicrobial Agents and Chemotherapy. 2012 ; Vol. 56, No. 7. pp. 3690-3699.
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abstract = "Arylimidamides (AIAs) have shown outstanding in vitro potency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2- pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good in vivo efficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility and in vivo antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51{\%} at an oral dose of 100 mg/kg/day X 5 and DB1955 reducing liver parasitemia by 57{\%} when given by the same dosing regimen. In a murine Trypanosoma cruzi infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46{\%} when given orally at 100 mg/kg/day X 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21{\%} decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.",
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T1 - Evaluation of arylimidamides DB1955 and DB1960 as candidates against visceral leishmaniasis and Chagas' disease

T2 - In vivo efficacy, acute toxicity, pharmacokinetics, and toxicology studies

AU - Zhu, Xiaohua

AU - Liu, Qiang

AU - Yang, Sihyung

AU - Parman, Toufan

AU - Green, Carol E.

AU - Mirsalis, Jon C.

AU - Soeiro, Maria De Nazaré Correia

AU - De Souza, Elen Mello

AU - Da Silva, Cristiane França

AU - Batista, Denise Da Gama Jaen

AU - Stephens, Chad E.

AU - Banerjee, Moloy

AU - Farahat, Abdelbasset A.

AU - Munde, Manoj

AU - Wilson, W. David

AU - Boykin, David W.

AU - Wang, Michael Zhuo

AU - Werbovetz, Karl A.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Arylimidamides (AIAs) have shown outstanding in vitro potency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2- pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good in vivo efficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility and in vivo antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day X 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murine Trypanosoma cruzi infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day X 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.

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