Combinatorial Chemistry & High Throughput Screening - Volume 8, Issue 7, 2005

Since the appearance of the first reports during the early nineties on non-peptidal small molecule libraries synthesized on solid phase supports, the fields of combinatorial chemistry and high throughput screening have experienced enormous progress and development. These techniques have become an essential part of the modern discovery process within the pharmaceutical industry and many pharmaceutical companies, inc Read More

The recent progress and future prospects for the successful application of combinatorial chemistry and high throughput screening within the agrochemical lead discovery process are outlined and discussed. Solid and solution phase library synthesis technologies are reviewed and compared, and the role and importance of bioavailability, diversity and virtual screening in rational library design are detailed.

During the past ten years combinatorial chemistry developed from a powerful synthetic methodology, providing large libraries of usually simple new chemical entities, to a comprehensive strategy presently covering a multitude of technologies across the whole workflow from hit generation to lead optimization. Thus combinatorial chemistry had a major impact not only on the pharmaceutical research but also with some dela Read More

In vivo high throughput screening (HTS) has been adopted by most of the larger crop protection companies as an important tool for the discovery of new agrochemicals. There has been a paradigm shift in capabilities from screening a few thousand compounds a year to several hundred thousand and the quantity of screening sample required has fallen dramatically. The unifying goal now bringing together screens and in Read More

The demand for new herbicides, insecticides and fungicides led to a steady increase in the number of compounds being tested to find novel market products. To keep pace with the rising workload, high throughput screening (HTS) technologies have been introduced. In agrochemical research miniaturised in vivo tests on whole real target organisms are now possible and are an integral part of the screening cascade. A comple Read More

Progress and developments made in microwave-assisted combinatorial synthesis and library production since 2002 are reviewed. The use of microwave technology in both solution and solid phase synthesis is discussed with special reference to agrochemical applications where appropriate.

A general route to a series of differentially substituted bicyclo[2,2,2]octenones has been developed, making use of the in situ intramolecular Diels Alder reaction of masked ortho-benzoquinones. This approach was used to synthesize a series of thirteen key acid-containing templates from which a solution phase discovery library of 1126 diverse amides was then constructed. The rigid polycyclic nature of the templates and the pre Read More

A novel class of highly active dihydropyridine miticides was prepared using a multicomponent reaction process. The initial lead was rapidly optimized using solution phase parallel synthesis techniques and a positional scanning approach. Detailed structure-activity relationships were developed for the amino and carbonyl components of the molecule and used to select the best candidates for broad field testing. The c Read More

Amino acids were immobilised by attaching them via a carbamate linker to Wang resin. These intermediates were converted to1-(1,3-benzoxazol-2-yl)alkanamines over three steps, followed by coupling with 4-alkyl-6-chloro-1,3,5-triazine-2-amines to furnish the desired N-[1-(1,3-benzoxazol-2-yl)alkyl]-6-alkyl- 1,3,5-triazine-2,4-diamines. Physico-chemical property profiles were used to support design and development of a comb Read More

The Automated Synthesis & Purification team at Bayer CropScience in Frankfurt provides services and support in the areas of synthesis and post synthesis activities for chemists. This article describes our workflow and the special robotic systems used. We produce small to medium sized compound libraries using liquid phase techniques. An example of a compound library taken from the herbicide area is given.

In order to gain a broad access to phosphinic acid derivatives, a palladium catalysed coupling reaction of aryl iodides with hypophosphorous acid derivatives has been developed on the solid phase. The resulting arylphosphorous acids (or esters) were derivatised using addition reactions with aldehydes, imines and isocyanates, to give phosphinic acids (or esters) with α-hydroxy , α-amino or aminoacyl groups attached to the ar Read More

The polymer assisted solution phase (PASP) synthesis of 4,5-dihydro-1,4-benzoxazepin-3(2H)-ones is described. Using salicylic aldehydes, α-bromo acetic acid esters, and primary amines as broadly variable building blocks, the target molecules were obtained in a straightforward manner. The use of polymer bound reagents and scavengers greatly simplified workup, and avoided the use of protecting groups. A small library was Read More

Potent new agonists of the insect muscarinic acetylcholine receptor (mAChR) have been discovered by synthesizing and screening a library of 225 oxime ether amines. Library evaluation was facilitated by the development of a high throughput test enabling the rapid determination of muscarinic agonist activity. The most interesting compounds were the thiadiazole 17 and the isoxazole 24 which were potent muscarinic agonists (E Read More

Jurgen Scherkenbeck was born in Remscheid, Germany in 1960 and obtained his diploma degree in chemistry from the Ruhr- University Bochum in 1985. His doctoral work in the field of natural product synthesis was performed under the supervision of Professor Peter Welzel at Bochum. In 1988 he took up a position within Central Research at Bayer AG in Leverkusen. During his industrial research career he has been involved in di Read More

Stephen Lindell was born in Ipswich, England in 1955 and obtained his bachelors degree in chemistry from Imperial College, London in 1977. His doctoral work was performed at the Research Institute for Medicine and Chemistry in Cambridge, Massachusetts under the supervision of Professor Sir Derek Barton and Dr. Robert Hesse. In 1982 he moved to Stanford University in Palo Alto, California to undertake post doctoral resea Read More