Design and Synthesis of Simplified Polyketide Analogs: New Modalities beyond the Rule of 5

Abstract

Natural products provide important lead structures for development of pharmaceutical agents or present attractive tools for medicinal chemistry. However, structurally complex and thus less accessible metabolites defying conventional drug‐like properties, as expressed by Pfizer's rule of five, have received less attention as medicinal leads. Traditionally, research focus has been on realizing total syntheses rather than developing more readily available analogs to resolve the critical supply issue. However, very recent studies with complex myxobacterial polyketides have demonstrated that considerable structural simplification may be realized with retention of biological potencies. The context, underlying rationale and importance of tailored synthetic strategies of three such case studies are presented, which may inspire further related activities and may eventually help exploiting the largely untapped biological potential of complex metabolites in general.

Challenges in natural product-based drug discovery assisted within silico-based methods

“…Numerous NP (macrocyclic) polyketides have been identified as very potent iPPIs. 133 It is worth mentioning that Lagorce et al 128 excluded from the ADMET profiling all NP-(derived) molecules on the basis that this class of molecules are not equally included in training and/or benchmark datasets of ADMET prediction models such as that of pkCSM. 118 …”

On drug discovery against infectious diseases and academic medicinal chemistry contributions

“…This means that the chemical libraries we can have today do not encompass the chemical space of drug-like compounds, far from it, apparently [88][89][90][91]. Concerning the definition of drug-like compounds, past the ground breaking Lipinski's rule of five [92], defining more precise criteria for the inclusion of a given chemical, possibly dependent on the target considered, remains an interesting research subject [88,[93][94][95][96]. A survey of the evolution of commercially available chemical libraries is also of real interest [97].…”