Andreas Link, Institute of Pharmacy, Faculty of Mathematics and Natural Sciences, Ernst-Moritz-Arndt-University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17487 Greifswald, Germany

Medicinal chemistry faces hard times due to the low success rates of research projects in the past decades [1]. Despite growing investment in research and development, the number of new drug approvals is declining steadily in many pharmaceutical companies. Among the multifaceted reasons for frequent failure are issues concerned with limited diversity, insufficient bioavailability, and toxicity on a molecular level [2]. Thus, in silico prediction of toxicity associated with molecular properties is developed within consortia of public private partnerships and phenomena such as phospholipidosis can already be forecasted with good accuracy, today. Aromatic molecules with a basic side chain that will be protonated inside cells will not be regarded appropriate for developmental candidates in the future. However, the necessity to exclude undesirable molecular properties has shown its dark side, as well. Drugs such as acetylsalicylic acid or penicillines would be regarded suspicious at present because of their ability to covalently interact with cellular structures. Chemically reactive molecules such as electrophiles have been discriminated against due to the concern that covalent interactions might be irreversible and out of control. This is currently changing and many medicinal chemists reinvent covalently binding compounds. These compounds will of course only be safe on a molecular level if it will be possible to design molecules with custom-tailored reactivity towards their therapeutic targets. If this can be achieved e.g. by appropriately substituted carbon-carbon double bonds, PD can be decoupled from PK and drugs with outstanding efficacy can be designed. The positive safety aspect of this strategy would be that only low drug concentrations would be necessary to be efficacious. A target protein could be blocked for hours after short contact with such a covalently binding drug while off-targets would only be minimally confronted with the active molecules for minutes.
Like electrophiles, reactive functional iodine substituents have been underrepresented in drug discovery programs, here due to safety concerns associated with the thyroid system. Now we know that we missed important interactions that could lead to valuable active compounds. Again, here we see a paradigm shift. State-of-the-art fragment screening libraries show an increasing content of halogen substituents [3]. In general, too much focus has been put on fat and flat aromatic molecules with a minor degree of functionalization as compared to bioactive compounds found in nature. Slim and shapely, not too flexible scaffolds decorated with benign functional groups are searched for, instead. A good starting point for the lead optimization study is characterized by fragment-like hit structures with three dimensional shape. This comprises sp3-rich backbones with defined stereochemistry and planarity-disrupting structural elements, frequently present in natural products. For example, functionalized cyclopentanes offer the opportunity to chart a part of conformational space that was hitherto underexplored [4]. The advantage that often comes along with such properties is a rigorous drop in crystallization tendency, which is advantageous during screening and of special importance in the later phases of galenics and pharmacokinetics. This also positively effects the water solubility, and thus is commonly beneficial for bioanalytical approaches.


1. Takashi Tsukamoto. Tough Times for Medicinal Chemists: Are We to Blame? ACS Med. Chem. Lett., 2013; 4, 369−370.

2. Tim Larsen and Andreas Link. A timely reassessment of early prediction in the bioavailability of orally administered drugs. Angew. Chem. Int. Ed., 2005; 44, 4432−4434.

3. Felix Wilde and Andreas Link. Advances in the design of a multipurpose fragment screening library. Expert Opin. Drug. Discov., 2013; 8, 597−606.

4. Yousheng Guan, Caterina Bissantz, Donald E. Bergstrom, and Andreas Link. 1,2,4-Trisubstituted Cyclopentanes as Platforms for Diversity. Arch. Pharm. Chem. Life Sci., 2012, 345, 677−686.