Medicinal chemistry is a biology-based and chemistry driven discipline. One of the main drivers in medicinal chemistry is synthetic chemistry.

We have seen great contributions to the process of drug discovery by synthetic chemistry. One might recall the era of natural product chemistry and of combinatorial chemistry. Nevertheless, one who has followed the developments in medicinal chemistry over the last decades gets the impression that the discipline is pushing against a wall without really breaking through.

The real need for this breakthrough is highlighted by the attrition rates: for nearly one third of newly assessed targets we are not able to find leads and – even more disturbing – one third of the leads can not be optimalized into early clinical candidates.

The burning question is how to bridge the gap between the structure of a compound and its properties. Which compound should be tested and which should be made next? For decades, medicinal chemistry has been linked to these questions.

Recent efforts are directed towards the making of properties rather than the making of chemical structures. The physical chemical properties to be made are being described in such a way that they can be handled by chemists. These developments will be discussed. One of them is the renaissance of natural products. The unique chemical space occupied by natural products has led to a renewed interest in them.

Finally, we will touch briefly upon a major disconnection between academia and pharmaceutical industry. In these two domains medicinal chemistry and in particular synthesis seem to have a different meaning. Solving this disconnection might bring closer an answer to the burning questions in medicinal chemistry.