Selecting Better Leads Lead-Likeness

A.D. were found in old mines, and sizable slag deposits suggest at least some level of lead exploitation during Roman times (2). By the careful selection of Roman lead artifacts likely to have been manufactured in Carthage, and the use of lead isotope analysis, it may be possible to confirm the use of Tunisian lead ores during the Roman period. In this preliminary study, analysis of 22 curse tablets by electron microprobe analysis (EMPA) and six tablets by thermal ionization mass spectrometry (TIMS) suggest that these artifacts might be used to better understand Roman lead use and trade. 

The selection and quality of a screening library with drug-like and lead-like structures is a critical endeavour. The features of drug-like and lead-like structures continue to be better defined, at the same time as the diversity of drug-like and lead-like molecular space continues to be explored and categorised. Other areas of development focus on the discovery of small molecules suitable for modulating protein-protein interactions, with a greater focus on natural product-like compounds. 

Knowing that we needed to develop a CNS drug, we then reduced the number of rotatable bonds of compound 11 and designed the rigid, compact 5,5 -diphenyl iminohydantoin core structure (compound 12) which, despite being only weakly active, now showed excellent lead-like properties with good LE, much better LLE, and an overall favorable profile with respect to cellular potency, selectivity, rat PK, and brain penetration (Fig. 4e). Thus, compound 12 was the superior choice for lead optimization. 

The diversity of catalyst chemistry and of process type makes it impossible to generalize as to what constitues a better catalyst, except to say that it is one which leads to products that are cheaper or better, or both. In many cases this is likely to be a result of greater selectivity rather than activity, but in single pathway reactions activity, and also the pattern of its change with time, becomes all important. The better catalyst can only therefore be defined in terms of the detailed context of the process for which an improvement is sought. 

We also performed a single-crystal X-ray structure analysis of this lead compound. The solid state structure of this compound depicted in Fig. 3-15 shows a half-boat-like ( sofa ) conformation with the 9-phenanthryl group in a quasi-axial or r/Mf/.v/-flagpole position, and the a, 3-unsaturated exocyclic ester in a s-cis conformation. This cleft-like conformation is advantageous for the creation of centers with a high recognition ability, since one enantiomer fits in better than the other thus leading to selectivity. 

The first and very simple solid contact polymeric sensors were proposed in the early 1970s by Cattrall and Freiser and comprised of a metal wire coated with an ion-selective polymeric membrane [94], These coated wire electrodes (CWEs) had similar sensitivity and selectivity and even somewhat better DLs than conventional ISEs, but suffered from severe potential drifts, resulting in poor reproducibility. The origin of the CWE potential instabilities is now believed to be the formation of a thin aqueous layer between membrane and metal [95], The dominating redox process in the layer is likely the reduction of dissolved oxygen, and the potential drift is mainly caused by pH and p02 changes in a sample. Additionally, the ionic composition of this layer may vary as a function of the sample composition, leading to additional potential instabilities. 

On the other hand, unsymmetrical internal alkynes usually lead to two different constitutional isomers. In compounds of type 18, selectivity in favor of 20 rather than 19 is observed (1 20) owing to the hydroxyl groups which might direct the deprotonation by directing the base to the closer propargylic methylene protons (Scheme 1.8) [37]. This chelate-like behavior, of course, becomes less significant as the tether increases for 21 and 22 the yield is better but the selectivity is reduced to only 1 5. 

---