- Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts
-
A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.
- Le Manach, Claire,Dam, Jean,Woodland, John G.,Kaur, Gurminder,Khonde, Lutete P.,Brunschwig, Christel,Njoroge, Mathew,Wicht, Kathryn J.,Horatscheck, André,Paquet, Tanya,Boyle, Grant A.,Gibhard, Liezl,Taylor, Dale,Lawrence, Nina,Yeo, Tomas,Mok, Sachel,Eastman, Richard T.,Dorjsuren, Dorjbal,Talley, Daniel C.,Guo, Hui,Simeonov, Anton,Reader, Janette,Van Der Watt, Mari?tte,Erlank, Erica,Venter, Nelius,Zawada, Jacek W.,Aswat, Ayesha,Nardini, Luisa,Coetzer, Theresa L.,Lauterbach, Sonja B.,Bezuidenhout, Belinda C.,Theron, Anjo,Mancama, Dalu,Koekemoer, Lizette L.,Birkholtz, Lyn-Marie,Wittlin, Sergio,Delves, Michael,Ottilie, Sabine,Winzeler, Elizabeth A.,Smith, Dennis,Fidock, David A.,Street, Leslie J.,Basarab, Gregory S.,Duffy, James,Chibale, Kelly
-
supporting information
p. 2291 - 2309
(2021/03/01)
-
- Synthetic method of fatty acid containing nitrogen heterocycle
-
The invention discloses a synthetic method of fatty acid containing nitrogen heterocycle. The synthetic method comprises the following steps: (S1) adding a heterocyclic compound with substitution of chloromethyl groups, a catalyst and a solvent DMF into a reaction kettle; (S2) introducing carbon dioxide to lead the pressure in the kettle to be 2-4MPa, adjusting and reacting for 10-16 hours at thetemperature of 40-50 DEG C; (S3) adding diluted hydrochloric acid into the reaction kettle to carry out acidification, using ethyl acetate for extraction, combining organic phases, carrying out rotaryevaporation to remove liquid, and further carrying out vacuum drying, thus obtaining the fatty acid containing nitrogen heterocycle. The synthetic method disclosed by the invention has the beneficialeffects that a one-pot method is adopted, the raw materials are easy to obtain, price is low, aftertreatment of products is also simpler, the universality for a substrate is also very high, and the promotion and application are easy.
- -
-
Paragraph 0015-0020; 0024
(2018/07/30)
-
- Synthesis and insecticidal activity of some 1,3,4-oxadiazoles derived from 2-chloropyridine-5-acetic acid
-
The synthesis of a number of 1,3,4-oxadiazoles 6a-e is described. 2-Chloropyridine-5-acetic acid 3 is prepared starting from easily available 2-chloro-5-chloromethylpyridine 1, via 2-chloro-5-cyanomethylpyridine 2. Esterification of 3 with methanol in the
- Holla, B. Shivarama,Prasanna,Poojary, Boja,Rao,Shridhara,Bhat, U. Ganesha
-
p. 864 - 868
(2007/10/03)
-
- COMPOUNDS USEFUL AS PESTICIDES
-
Compounds useful to control pests are provided.
- -
-
-