55474-40-3Relevant articles and documents
Ametoctradin is a Potent Qo Site Inhibitor of the Mitochondrial Respiration Complex III
Zhu, Xiaolei,Zhang, Mengmeng,Liu, Jingjing,Ge, Jingming,Yang, Guangfu
, p. 3377 - 3386 (2015/04/14)
Ametoctradin is a new Oomycete-specific fungicide under development by BASF. It is a potent inhibitor of the bc1 complex in mitochondrial respiration. However, its detailed action mechanism remains unknown. In the present work, the binding mode of ametoctradin was first uncovered by integrating molecular docking, MD simulations, and MM/PBSA calculations, which showed that ametoctradin should be a Qo site inhibitor of bc1 complex. Subsequently, a series of new 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized to further understand the substituent effects on the 5- and 6-position of 1,2,4-triazolo[1,5-a]pyrimidine. The calculated binding free energies (ΔGcal) of newly synthesized analogues as Qo site inhibitors correlated very well (R2 = 0.96) with their experimental binding free energies (ΔGexp). Two compounds (4a and 4c) with higher inhibitory activity against porcine SQR than ametoctradin were successfully identified. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a new promising bc1 inhibitor.
Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine resistant Plasmodium falciparum
Tarnchompoo, Bongkoch,Sirichaiwat, Chawanee,Phupong, Worrapong,Intaraudom, Chakapong,Sirawaraporn, Worachart,Kamchonwongpaisan, Sumalee,Vanichtanankul, Jarunee,Thebtaranonth, Yodhathai,Yuthavong, Yongyuth
, p. 1244 - 1252 (2007/10/03)
The reduced binding of pyrimethamine to Serl08Asn (S108N) mutants of parasite dihydrofolate reductase (DHFR), which forms the basis of resistance of Plasmodium falciparum to pyrimethamine, is largely due to steric constraint imposed by the bulky side chain of N108 on Cl of the 5-p-Cl-phenyl group. This and other S108 mutants with bulky side chains all showed reduced binding to pyrimethamine and cycloguanil. Less effect on binding to some bulky mutants was observed for trimethoprim, with greater flexibility for the 5-substituent. S108N DHFR also binds poorly with other pyrimethamine derivatives with bulky groups in place of the p-Cl, and the binding was generally progressively poorer for the double (C59R+S108N) mutant. Removal of the p-Cl or replacement with m-Cl led to better binding with the mutant DHFRs. Pyrimethamine analogues with unbranched hydrophobic 6-substituents showed generally good binding with the mutant DHFRs. A number of compounds were identified with high affinities for both wild-type and mutant DHFRs, with very low to no affinity to human DHFR. Some of these compounds show good antimalarial activities against pyrimethamine-resistant P. falciparum containing the mutant DHFRs with low cytotoxicity to three mammalian cell lines.
