Dataset Information

Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors.

ABSTRACT: Utilizing a target repurposing and parasite-hopping approach, we tested a previously reported library of compounds that were active against Trypanosoma brucei, plus 31 new compounds, against a variety of protozoan parasites including Trypanosoma cruzi, Leishmania major, Leishmania donovani, and Plasmodium falciparum. This led to the discovery of several compounds with submicromolar activities and improved physicochemical properties that are early leads toward the development of chemotherapeutic agents against kinetoplastid diseases and malaria.

SUBMITTER: Singh B

PROVIDER: S-EPMC7073875 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors.

Singh Baljinder B Bernatchez Jean A JA McCall Laura-Isobel LI Calvet Claudia M CM Ackermann Jasmin J Souza Julia M JM Thomas Diane D Silva Everton M EM Bachovchin Kelly A KA Klug Dana M DM Jalani Hitesh B HB Bag Seema S Buskes Melissa J MJ Leed Susan E SE Roncal Norma E NE Penn Erica C EC Erath Jessey J Rodriguez Ana A Sciotti Richard J RJ Campbell Robert F RF McKerrow James J Siqueira-Neto Jair L JL Ferrins Lori L Pollastri Michael P MP

ACS medicinal chemistry letters 20200110 3

Utilizing a target repurposing and parasite-hopping approach, we tested a previously reported library of compounds that were active against Trypanosoma brucei, plus 31 new compounds, against a variety of protozoan parasites including Trypanosoma cruzi, Leishmania major, Leishmania donovani, and Plasmodium falciparum. This led to the discovery of several compounds with submicromolar activities and improved physicochemical properties that are early leads toward the deve ...[more]

PMID: 32184953

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Project description:The use of herbicide safeners can significantly alleviate herbicide injury to protect crop plants and expand the application scope of the existing herbicides in the field. Sanshools, which are well known as spices, are N-alkyl substituted compounds extracted from the Zanthoxylum species and have several essential physiological and pharmacological functions. Sanshools display excellent safener activity for the herbicide metolachlor in rice seedlings. However, the high cost of sanshools extraction and difficulties in the synthesis of their complicated chemical structures limit their utilization in agricultural fields. Thus, the present study designed and synthesized various N-alkyl amide derivatives via the scaffold-hopping strategy to solve the challenge of complicated structures and find novel potential safeners for the herbicide metolachlor. In total, 33 N-alkyl amide derivatives (2a-k, 3a-k, and 4a-k) were synthesized using amines and saturated and unsaturated fatty acids as starting materials through acylation and condensation. The identity of all the target compounds was well confirmed by 1H-NMR, 13C-NMR, and high-resolution mass spectrometry (HRMS). The primary evaluation of safener activities for the compounds by the agar method indicated that most of the target compounds could protect rice seedlings from injury caused by metolachlor. Notably, compounds 2k and 4k displayed excellent herbicide safener activities on plant height and demonstrated relatively similar activities to the commercialized compound dichlormid. Moreover, we showed that compounds 2k and 4k had higher glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO) activities in rice seedlings, compared to the metolachlor treatment. In particular, 2k and 4k are safer for aquatic organisms than dichlormid. Results from the current work exhibit that compounds 2k and 4k have excellent crop safener activities toward rice and can, thus, be promising candidates for further structural optimization in rice protection.

Dataset Information

Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors.

Publications

Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors.

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