Synthesis and in vitro anti- Toxoplasma gondii activity of a new series of aryloxyacetophenone thiosemicarbazones
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ORIGINAL ARTICLE
Synthesis and in vitro anti‑Toxoplasma gondii activity of a new series of aryloxyacetophenone thiosemicarbazones Mahsa Ansari1 · Mahbobeh Montazeri2,3,4 · Ahmad Daryani2,4 · Kaveh Farshadfar5 · Saeed Emami6 Received: 27 May 2019 / Accepted: 7 August 2019 © Springer Nature Switzerland AG 2019
Abstract A new series of aryloxyacetophenone thiosemicarbazones 4a–q have been synthesized as anti-Toxoplasma gondii agents. All compounds showed significant inhibitory activity against T. gondii-infected cells ( IC50 values 1.09–25.19 μg/mL). The 4-fluorophenoxy derivative (4l) was the most potent compound with the highest selectivity toward host cells (SI = 19), being better than standard drug pyrimethamine. SAR study indicated that the concurrence of proper substituents on both aryl ring of phenoxyacetophenone is important for potency and safety profile. Further in vitro experiments with the representative compounds 4l and 4p revealed that these compounds at the concentration of 5 μg/mL can significantly reduce the viability of T. gondii tachyzoites, as well as their infectivity rate and intracellular proliferation, comparable to those of pyrimethamine. Graphic abstract
Keywords Acetophenone derivatives · Anti-apicomplexan · Thiosemicarbazones · Toxoplasmosis · Toxoplasma gondii
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-019-09986-9) contains supplementary material, which is available to authorized users. * Saeed Emami [email protected]; [email protected] Extended author information available on the last page of the article
Toxoplasma gondii (T. gondii), the ubiquitous parasitic protozoan belonging to phylum Apicomplexa, is the etiologic agent of toxoplasmosis. This successful obligate intracellular parasite can infect all warm-blooded vertebrates such as humans, livestock, birds and marine mammals [1]. It is estimated that up to one-third of the world’s population is infected with T. gondii specifically in developing countries
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[2]. Although the infection is asymptomatic in most immunocompetent people with normal immunity, significant morbidity and mortality may especially occur in congenitally infected and immunocompromised individuals such as HIVpositive, cancer or organ transplant human patients [3]. The recommended drugs for treatment of toxoplasmosis are the combination of pyrimethamine (an inhibitor of dihydrofolate reductase) and sulfonamides such as sulfamethoxazole or sulfadiazine which inhibit dihydropteroate synthetase in the folate synthesis pathway. In addition, other drugs such as clarithromycin, azithromycin and atovaquone can be used for treatment of toxoplasmosis [4, 5]. However, current chemotherapy for toxoplasmosis is often associated with serious side effects including hypersensitivity, hematological toxicity, teratogenicity and allergic reactions. Most of chemotherapeutic agents are only effective in the acute phase of the disease and cannot eliminate intracellular parasit
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