Applications in Medicinal Chemistry

In the top left case, a palladium-catalysed nitrile coupling was rapidly executed by 2 min of microwave irradiation, while the phenyl-imidazole moiety was created using a very slnggish Ullman-type of reaction. 

---

The Corey-Chaykovsky reaction incited some applications in medicinal chemistry. During the synthesis of analogs of fluconazole, an azole antifungal agent, treatment of 49 with 1 led to the corresponding epoxide, which was subsequently... 

During the last decade, density-functional theory (DFT)-based approaches [1, 2] have advanced to prominent first-principles quantum chemical methods. As computationally affordable tools apt to treat fairly extended systems at the correlated level, they are also of special interest for applications in medicinal chemistry (as demonstrated in the chapters by Rovira, Raber et al. and Cavalli et al. in this book). Several excellent text books [3-5] and reviews [6] are available as introduction to the basic theory and to the various flavors of its practical realization (in terms of different approximations for the exchange-correlation functional). The actual performance of these different approximations for diverse chemical [7] and biological systems [8] has been evaluated in a number of contributions. 

Here, we will first give an introduction to the basic ideas underlying the Car-Parrinello method, especially addressed to complete newcomers in the field. We will then try to outline some of the recent methodological extensions, with particular emphasis on aspects with potential interest for applications in medicinal chemistry. The power and limitations of these new modeling tools will be illustrated with few selected examples. 

Schmidt, R.R. (1992) Carbohydrates -Synthetic Methods and Application in Medicinal Chemistry (eds A. Hasegawa, H. Ogura and T. Suami), Kodanasha Scientific, Tokyo, pp. 66-88. 

L. Hough and A. C. Richardson, From sugars to morpholines, spiro-acetals and alkaloids, in H. Ogura, A. Hasegawa, and T. Suami, (Eds.), Carbohydrates Synthetic Methods and Applications in Medicinal Chemistry, Kodansha, Tokyo, 1992, pp. 108-119. 

Asymmetric electrophilic fluorination has already found application in medicinal chemistry. For example, the enantioselective synthesis of a fluorooxindole, Maxipost (BMS-204352), has been reported. This compound is an effector for opening calcium channels and is currently in development for the treatment of cerebral ischemia (Figure 2.5). ... 

Major advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives appeared in 1999. Solid-phase combinatorial chemistry of benzimidazoles and tiiazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. In medicinal chemistry, synthesis and structure-activity relationship (SAR) studies utilizing these core structures have been exploited heavily. The physical organic chemistry of pyrazoles and imidazoles continue. 

Furukawa K, Kobata A (1992) Cell surface carbohydrates - their involvement in cell adhesion. In Ogura H (ed) Carbohydrates - synthetic methods, applications in medicinal chemistry. VCH, Weinheim, p 369... 

F Ooms (2000) Molecular Modeling and Computer Aided Drug Design Examples of their Applications in Medicinal Chemistry, Curr Med Chem 7 141-158... 

Medicinal Chemistry of Bioactive Natural Products provides a much-needed survey of biaactive natural pfcxjucts and their applications in medicinal chemistry. This comprehensive reference features articles by some of the world s leading scientists in the field on discovery, structure elucidation, and elegant synthetic strategies—developed for natural products— with an emphasis on the structure activity relationship of bioactive natural products. The topics have been carefully chosen on the basis of relevance to current research and to importance as cliniciafly useful agents. 

Enantioselective fluorination reactions catalyzed by chiral palladium enolate complexes have been the subject of considerable research . For instance, the fluorination of acyclic /S-ketoester (88, equation 24) using Af-fluorobenzenesulfonimide (NFSI) gave product 89 in high yields and with excellent enantioselectivity (ee up to 94%) . This reaction can be carried out in environmentally benign alcoholic solvents and provides valuable synthetic building blocks that find applications in medicinal chemistry, chemical biology and material sciences. 

Perhaps the most popular example of 3D-QSARis the comparative molecular field analysis (CoMFA), developed by Cramer et al. (40), which has elegantly combined the power of 3D molecular modeling and partial least-square (PLS) optimization technique (41, 42) and found wide applications in medicinal chemistry and toxicity analysis (see below). Most of... 

Ogura H, Hasegawa A, Suami T (eds) (1992) Carbohydrates. Synthetic methods and applications in medicinal chemistry. VCH and Kodansha, Weinheim and Tokyo Kovac P (ed) (1994) Synthetic oligosaccharides. Indispensable probes for the life sciences. ACS Symposium Series 560. American Chemical Society, Washington Whitfield DM, Douglas SP (1996) Glycoconjugate J 13 5... 

Linhardt RJ (1992) Chemical and enzymatic methods for the depolymerization and modification of heparin. In Ogura H (ed) Carbohydrates—synthetic methods and application in medicinal chemistry. KodanshaWCH Publishers, Tokyo, p 387... 

Ooms F. Molecular modelling and computer aided drug design. Examples of their application in medicinal chemistry. Curr Med Chem 2000 7 141-58. 

---