Agrochemical lead optimization by scaffold hopping

Abstract

Scaffold hopping, the exchange of a specific portion of a potential active ingredient with another substructure with the aim of finding isofunctional molecular structures with significantly different molecular backbones, often offers the chance in lead discovery or optimization to mitigate problems related to toxicity, intellectual property, and insufficient potency or stability. Scaffold hopping tools such as isosteric ring replacement including 1,3 nitrogen shift and cyclic imine-amide isosterism, but also ring opening and ring closure approaches, functional group isosterism, reversion of functional groups, chain shortening, chain lengthening, and scaffolds delivered by natural products, have become a permanent fixture of the innovation and optimization process in crop protection research. Their appropriate use will be explained through examples of success stories in the field of agrochemistry. Analogies to, but also differences from, the main categories of scaffold hopping in medicinal drug discovery are discussed. © 2017 Society of Chemical Industry.

Structural similarities between some common fluorophores used in biology and marketed drugs, endogenous metabolites, and natural products

“…In a d d ition , w e n ote th a t m olecu les w ith d iffer en t sca ffold s m a y b e q u ite sim ila r ; in th e ch em in for m a tics liter a tu r e th is is kn ow n a s 'sca ffold h op p in g' (e.g. [65][66][67][68][69][70]).…”

Computer-Aided Drug Design in Epigenetics

“…Scaffold hopping was proposed as a promising strategy to look for novel molecular entities with similar three dimensional conformations and properties (Schneider et al, 1999 ). As a shape-based three dimensional structure superposition method, it has been extensively used to generate potential alternatives of known compounds based on the bioisosteric replacement of core motif within molecules (Sun et al, 2012 ; Lamberth, 2017 ). In 2016, Yue et al applied a shape-based scaffold hopping approach to reposition approved drugs targeting the Menin-MLL1 interaction (Yue et al, 2016 ).…”

Spiro N‐methoxy piperidine ring containing aryldiones for the control of sucking insects and mites: discovery of spiropidion

“…Strategies in scaffold hopping 5 and bioisosteric replacement of functional groups 6 offer great opportunities to explore and optimize many cross-functional parameters in drug design. We aim herein to describe how the chemistry around an underexplored building block from the 1960s was developed towards a novel non-neuronal acting active ingredient against key economic pests, especially those sucking from the phloem of plant vascular bundles in growing shoots.…”