Unique Insertion Mechanisms of Bis-dehydro-β-diketiminato Silylene

The unique insertion reactions of the first, stable six-membered-ring silylene ({HC[CMeN(R)]₂}Si, R = 2,6-diisopropylphenyl) with eight reactants were investigated by the B3LYP/cc-pVTZ method. The initial step (<b>IS</b>) of all the reactions is the formation of an intermediate 1,4-adduct, <b>IM</b>, which will be then the starting point toward the different final states (<b>FS</b>). In this study three different mechanisms were found and studied to the 1,4-adduct and six reaction paths from the 1,4-adduct to the final products. On the basis of the results, the different reaction paths, the experimental insertion products, and the special reactivity of the six-membered-ring silylene have been explained

Impact of Lipophilic Efficiency on Compound Quality

Lipophilic efficiency indices such as LLE and LELP were suggested to support balanced optimization of potency and ADMET profile. Here we investigated the performance of LLE and LELP on multiple data sets representing different stages of drug discovery including fragment and HTS hits and leads, development candidates, phase II compounds, and launched drugs. Analyzing their impact on ADME and safety properties and binding thermodynamics, we found that both LLE and LELP help identifying better quality compounds. LLE is sensible for the development stages but does not prefer fragment-type hits, while LELP has an advantage for this class of compounds and discriminates preferred starting points effectively. Both LLE and LELP have significant impact on ADME and safety profiles; however, LELP outperforms LLE in risk assessment at least on the present data set. On the basis of the results reported here, monitoring lipophilic efficiency metrics could contribute significantly to compound quality and might improve the output of medicinal chemistry programs