Parasitic platyhelminths are responsible for serious infectious diseases, such as schistosomiasis, which affect humans as well as animals across vast regions of the world. The drug arsenal available for the treatment of these diseases is limited; for example, praziquantel is the only drug currently used to treat ≥240 million people each year infected with Schistosoma spp., and there is justified concern about the emergence of drug resistance. In this study, we screened biarylalkyl carboxylic acid derivatives for their antischistosomal activity against S. mansoni. These compounds showed significant influence on egg production, pairing stability, and vitality. Tegumental lesions or gut dilatation was also observed. Substitution of the terminal phenyl residue in the biaryl scaffold with a 3-hydroxy moiety and derivatization of the terminal carboxylic acid scaffold with carboxamides yielded compounds that displayed significant antischistosomal activity at concentrations as low as 10 μm with satisfying cytotoxicity values. The present study provides detailed insight into the structure-activity relationships of biarylalkyl carboxylic acid derivatives and thereby paves the way for a new drug-hit moiety for fighting schistosomiasis.
Infectious diseases caused by chlamydia or schistosomes are a major health problem worldwide, and particularly so in developing countries. The lack of appropriate vaccines renders the search for potent natural products against these disease-causing agents an urgent endeavor. Sponge-associated actinomycetes represent a rich reservoir for natural products. Among them, members of the genus Streptomyces are capable of synthesizing an impressive array of diverse natural products with a wide variety of biological activities. The naphthacene glycoside SF2446A2 was isolated from the calcium alginate beads culture of Streptomyces sp. strain RV15 that had originally been obtained from the Mediterranean sponge Dysidea tupha. Its structure was identified by spectroscopic analysis and MS and comparison with the literature data. SF2446A2 showed inhibitory activity against Chlamydia trachomatis and was able to inhibit the primary infection in a dose-dependent manner, as well as progeny formation. Moreover, it caused disruptive effects on the surface area of Schistosoma mansoni and affected the gonads by impairing oogenesis and spermatogenesis. Our current study demonstrates that sponge-associated actinomycetes are capable of providing compounds with new pharmacological activities and with relevance to drug discovery.
Schistosomes and other parasitic platyhelminths cause infectious diseases of worldwide significance for humans and animals. Despite their medical and economic importance, vaccines are not available and the number of drugs is alarmingly limited. For most platyhelminths including schistosomes, Praziquantel (PZQ) is the commonly used drug. With respect to its regular application in mass treatment programs, however, there is increasing concern about resistance development.Previous studies demonstrated that inhibitors used to treat non-parasitic human diseases may be useful to be tested for their effects on parasites. To this end, we focused on biarylalkyl carboxylic acids (BACAs) as basis, which had been shown before to be interesting candidates in the context of finding alternative approaches to treat diabetes mellitus. We tested 32 chemically modified derivatives of these substances (biarylalkyl carboxylic acid derivatives (BACADs)) for their effects on adult Schistosoma mansoni in vitro. Treatment with 18 BACADs resulted in egg production-associated phenotypes and reduced pairing stability. In addition, 12 of these derivatives affected vitality and/or caused severe tegument damage, gut dilatation, or other forms of tissue disintegration which led to the death of worms. In most cases (10/12), one derivative caused more than one phenotype at a time. In vitro experiments in the presence of serum albumin (SA) and alpha-acidic glycoprotein (AGP) indicated a varying influence of these blood components on the effects of two selected derivatives. The variety of observed phenotypes suggested that different targets were hit. The results demonstrated that BACADs are interesting substances with respect to their anti-schistosomal effects.
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