查看更多>>摘要：The discovery and development of new agrochemicals has become a difficult and resource-intensive undertaking.In the search for novel active ingredients,the scaffold of a lead often needs to be changed to allow for the respective chemistry class to be optimized.The changes are typically a consequence of issues related to an insufficient level of activity,blocked intellectual property,high complexity of lead compounds(e.g.,natural products),unfavorable metabolic stability,non-ideal physicochemical properties,adverse findings in toxicology studies,and other similar reasons.Scaffold hopping,the replacement of one part of a molecule with another scaffold,and the bioisosteric exchange of rings and functional groups offer the opportunity to either improve the properties of a compound or find similar potent compounds that exist in a new chemical space.
查看更多>>摘要：Piperazine and homopiperazine are well-studied heterocycles in drug design that have found gainful application as scaffolds and terminal elements and for enhancing the aqueous solubility of a molecule.The optimization of drug candidates that incorporate these heterocycles in an effort to refine potency,selectivity,and developabiliry properties has stimulated the design and evaluation of a wide range of bioisosteres that can offer advantage.In this review,we summarize the design and application of bioisosteres of piperazine and homopiperazine that have almost exclusively been in the drug design arena.While there are ~100 approved drugs that incorporate a piperazine ring,only a single marketed agricultural product is built on this heterocycle.As part of the review,we discuss some of the potential reasons underlying the relatively low level of importance of this heterocycle to the design of agrochemicals and highlight the potential opportunities for their use in contemporary research programs.
查看更多>>摘要：Applications of piperazine and homopiperazine in drug design are well-established,and these heterocycles have found use as both scaffolding and terminal elements and also as a means of introducing a water-solubilizing element into a molecule.In the accompanying review(I0.1021/acs.jafc.2c00726),we summarized applications of piperazine and homopiperazine and their fused ring homologues in bioactive compound design along with illustrations of the use of 4-substituted piperidines and a sulfoximine-based mimetic.In this review,we discuss applications of pyrrolidine-and fused-pyrrolidine-based mimetics of piperazine and homopiperazine and illustrate derivatives of azetidine that include stretched and spirocyclic motifs,along with applications of a series of diarninocycloalkanes.
查看更多>>摘要：Reverting the orientation of a functional group by exchanging molecular parts of it is an important scaffold hopping manipulation,as biologically active compounds and their analogs,which underwent such a transformation,are often similar in shape and physicochemical properties and therefore likely in their potency as well.This review will demonstrate,how the inversion of carboxamides,sulfonamides,carbamates,oximes,hydrazones,0,S-acetals,and ethers led to the discovery of highly active agrochemicals.
查看更多>>摘要：Inserting small flexible linkers of only one-to three-atom chain lengths into a molecular backbone is an important scaffold hopping manipulation.Analogues derived from biologically active compounds through the utilization of such a strategy are often similar in shape and physicochemical properties and,therefore,likely to exhibit similar potency.This review will demonstrate how the elongation with oxygen,amino,methylene,ethylene,vinyl,ethynyl,and CH2O bridges led to the discovery of highly active agrochemicals.
查看更多>>摘要：Trifluoromethylpyridine(TFMP) is a biologically active fragment formed by connecting trifluoromethyl and pyridine ring.As a result of its unique physical and chemical properties and outstanding biological activity,a variety of pesticide compounds with the TFMP fragment have been discovered and marketed and have played important roles in crop protection research.It is therefore a timely and valuable task to summarize the rationality on how to create new molecules containing TFMP fragments based on the structure-activity relationships,design mentality,and potential mechanism.This review gives a brief summary on the pesticides containing TFMP fragments in the past 5 years and introduces the latest progress of our group in this field.The aim is to provide readers with a convenient route to touch this topic and hopefully serve some educational purpose for graduate students as well.
查看更多>>摘要：Macrocyclic natural products and their derivatives are a valuable source for biologically active crop protection products and have had significant impact on the development of conventional agrochemicals.However,they can be challenging starting points for lead-generation efforts because of their size,structural complexity,and developability.Using molecular modeling and electrostatic analysis,alternative bicyclic isosteres were identified as replacements for the antifungal nine-membered macrocycle UK-2A.By application of a structure-based conformational approach,a series of heterocyclic replacements were derivatized to deliver promising fungicidal activity and scaffold bioisosteres were further diversified to investigate structure-activity relationships.
查看更多>>摘要：The application of agrochemicals is critical to global food safety.Nowadays,environmentally friendly green agrochemicals are the trend in field crop protection.The research and development of nematicides absorbed more attention as a typical representation of agrochemicals.This review describes the origin of recently commercialized nematicides,the application of bioisosterism and scaffold hopping in the discovery and optimization of agrochemicals,especially nematicides,and novel bioisosteric design strategies for the identification of fluensulfone analogues.Pesticide repurposing,high-throughput screening,computer-aided drug design,and incorporation of known pharmacophoric fragments have been the most successful approach for the discovery of new nematicides.As outlined,the strategies of bioisosteric replacements and scaffold hopping have been very successful approaches in the search for new nematicides for sustainable crop protection.In the exploration of novel fluensulfone analogues with nematicidal activity,bioisosteric replacement of sulfone by amide,chain extension by insertion of a methylene group,and reversal of the amide group have proven to be successful approaches and yielded new and highly active fluensulfone analogues.These attempts might result in compounds with an optimal balance of steric,hydrophobic,electronic,and hydrogen-bonding properties and contribute to deal with the complex problem during the research and development of new nematicides.Further ideas are also put forward to provide new approaches for the molecular design of nematicides.
查看更多>>摘要：Mesoionic pyrido[l,2-a]pyrimidinones are a unique class of heterocyclic compounds.Compounds from this class with a n-propyl group substituted at the 1 position of the mesoionic core were discovered with interesting insecticidal activity in our screen.In this overview,we showcase how a bioisosteric replacement strategy was applied during the discovery and optimization of this class of compounds.Through exploring various substituents at the 1 position,evaluating a variety of mesoionic bicyclic ring scaffolds,and examining substituents on the phenyl group at the 3 position of the mesoionic core as well as substituents on the mesoionic ring skeleton,many compounds were discovered with excellent hopper activity or potent activity against a wide range of Lepidoptera.Ultimately,dicloromezotiaz was identified for commercial development to control a broad spectrum of lepidopteran pests.
查看更多>>摘要：Bioisosteric replacement has been proven to be a powerful strategy in life science research.In this review,general aspects of carbon-silicon bioisosteric substitution and its applications in pharmaceutical and crop protection research are described.Carbon and their silicon analogues possess similar intrinsic properties.Replacing carbon with silicon in pharmaceuticals and pesticides has shown to result in positive effects on efficacy and selectivity,physicochemical properties,and bioavailability and also to eliminate or improve human or environmental safety properties as well as to provide novelty and new intellectual property in many cases.Furthermore,the application of carbon-silicon substitution in the search for new complex II acaricides is highlighted.This research led to the discovery of sila-cyflumetofen 23a and other silicon-containing analogues of cyflumetofen that match or exceed the acaricidal activity of cyflumetofen.The molecular design strategy,synthetic aspects,biological activity,computational modeling work,and structure-activity relationships will be discussed.
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