ABSTRACT
Triketones are suitable compounds for 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition and are important compounds for eliminating agricultural weeds. We report herein quantitative structure-activity relationship (QSAR) modelling and docking studies for a series of triketone-quinoline hybrids and 2-(aryloxyacetyl)cyclohexane-1,3-diones with the aim of proposing new chemical candidates that exhibit improved performance as herbicides. The QSAR models obtained were reliable and predictive (average r2, q2, and r2pred of 0.72, 0.51, and 0.71, respectively). Guided by multivariate image analysis of the PLS regression coefficients and variable importance in projection scores, the substituent effects could be analysed, and a promising derivative with R1 = H, R2 = CN, and R3 = 5,7,8-triCl at the triketone-quinoline scaffold (P18) was proposed. Docking studies demonstrated that π-π stacking interactions and specific interactions between the substituents and amino acid residues in the binding site of the Arabidopsis thaliana HPPD (AtHPPD) enzyme support the desired bioactivity. In addition, compared to a benchmark commercial triketone (mesotrione), the proposed compounds are more lipophilic and less mobile in soil rich in organic matter and are less prone to contaminate groundwater.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase , Arabidopsis , Herbicides , Quinolines , Quantitative Structure-Activity Relationship , Models, Molecular , Herbicides/pharmacology , Herbicides/chemistry , Plant Weeds/metabolism , Arabidopsis/chemistry , 4-Hydroxyphenylpyruvate Dioxygenase/chemistry , 4-Hydroxyphenylpyruvate Dioxygenase/metabolism , Enzyme Inhibitors/chemistryABSTRACT
Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Flaviviridae/enzymology , Peptides/chemistry , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/chemistry , Viral Proteins/chemistry , Animals , Flaviviridae Infections/drug therapy , Humans , Molecular Structure , Viral Proteins/antagonists & inhibitorsABSTRACT
Hepatitis C, Dengue and West Nile virus are some of the most important flaviviruses, that share one important serine protease enzyme. Serine proteases are the most studied class of proteolytic enzyme and, in these cases, a primary target for drug discovery. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N- t-Boc amino acid esters derived of isomannide as potential serine proteases inhibitors.
