Abstract
Echinococcosis is a serious helminthic zoonosis with a great impact on human health and livestock husbandry. However, the clinically used drugs (benzimidazoles) have a low cure rate, so alternative drugs are urgently needed. Currently, drug screenings for echinococcosis are mainly phenotype-based, and the efficiency of identifying active compounds is very low. With a pharmacophore model generated from the structures of active amino alcohols, we performed a virtual screening to discover novel compounds with anti-echinococcal activity. Sixty-two compounds from the virtual screening were tested on Echinococcus multilocularis protoscoleces, and 10 of these compounds were found to be active. After further evaluation of their cytotoxicity, S6 was selected along with two active amino alcohols for in vivo pharmacodynamic and pharmacokinetic studies. At the two tested doses (50 and 25 mg/kg), S6 inhibited the growth of E. multilocularis in mice (14.43 and 9.53%), but no significant difference between the treatment groups and control group was observed. Treatment with BTB4 and HT3 was shown to be ineffective. During the 28 days of treatment, the death of mice in the mebendazole, HT3, and BTB4 groups indicated their toxicity. The plasma concentration of S6 administered by both methods was very low, with the Cmax being only 1 ng/ml after oral administration and below the detection limit after intramuscular administration. In addition, the plasma concentrations of BTB4 and HT3 in vitro did not reach high enough levels to kill the parasites. The toxicities of these two amino alcohols indicated that they are not suitable for further development as anti-echinococcal drugs. However, further attempts should be made to increase the bioavailability of S6 and modify its structure. In this study, we demonstrate that pharmacophore-based virtual screenings with high drug identification efficiency could be used to find novel drugs for treating echinococcosis.
Highlights
Echinococcus granulosus and E. multilocularis are the most important Echinococcus species currently affecting humans; in the larval stages, these species cause cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively (Eckert et al, 2001)
Hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), lipid hydrogen bond acceptor (LHBA), hydrophobic feature (HC), hydrophobic aliphatic (HAL), hydrophobic aromatic (HAR), positive ionizable (PI) and aromatic ring (AR) were selected as the building blocks for generating the pharmacophore model
The pharmacophore model HipHop-Hypo03 was considered the best chemical hypothesis because the model was better at distinguishing active from inactive compounds
Summary
Echinococcus granulosus and E. multilocularis are the most important Echinococcus species currently affecting humans; in the larval stages, these species cause cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively (Eckert et al, 2001). CE occurs worldwide, while AE is confined to the Northern Hemisphere (WHO/Department of Control of Neglected Tropical Diseases, 2013). The growth of these parasites in patients is slow, and until the parasites grow to an extent that triggers clinical signs, which takes many years, their growth remains asymptomatic (Moro and Schantz, 2009). The drugs currently available in clinical settings are primarily limited to benzimidazoles (BMZ), albendazole and mebendazole, and the chemotherapy usually lasts 3 to 6 months but can last even longer (Lacey, 1990; Hemphill and Muller, 2009). No other medications to treat echinococcosis have been approved in the last 30 years; it is essential to find alternative chemotherapy strategies for treating this disease
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