Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

Abstract

Natural products (NPs) are an excellent source of biologically active molecules that provide many biologically biased features that enable innovative designing of synthetic compounds. NPs are characterized by high content of sp 3-hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural diversity. To date, several approaches have been implemented for mapping and navigating into the chemical space of NPs to explore the different aspects of chemical space. The approaches providing novel opportunities to synthesize NP-inspired compound libraries involve NP-based fragments and ring distortion strategies. These methodologies allow access to areas of chemical space that are less explored, and consequently help to overcome the limitations in the use of NPs in drug discovery, such as lack of accessibility and synthetic intractability. In this review, we describe how NPs have recently been used as a platform for the development of diverse compounds with high structural and stereochemical complexity. In addition, we show developed strategies aiming to reengineer NPs toward the expansion of NP-based chemical space by fragment-based approaches and chemical degradation to yield novel compounds to enable drug discovery.

Absorption matters: A closer look at popular oral bioavailability rules for drug approvals

“…Complementary, in earlier studies, it has been observed that natural products are more likely to possess aliphatic rings, with a higher number of sp3-hybridized bridged atoms, more nitrogen atoms and chiral centers than synthetic drugs. Thus, it can be argued that natural products provide advantageous scaffolds in the development of drugs, but no analogous or systematic rule for the drug-likeness of natural products has been derived yet [31][32][33].…”

Synthesis of Pyridoxine-Derived Dimethylpyridinols Fused with Aminooxazole, Aminoimidazole, and Aminopyrrole

“…Phenotypic screening campaigns have long been crucial to the identification of biologically active small molecules in conjunction with target-based approaches [ 1 , 2 ]. Because of their biological relevancy and favorable physicochemical properties, novel scaffolds from nature are frequently used to inspire the preparation of compound collections for phenotypic screening [ 3 , 4 , 5 , 6 ]. Pyridoxine ( 1 ) is a form of vitamin B 6 that scavenges reactive oxygen species and regulates diverse cellular metabolisms, including amino acid biosynthesis and fatty acid biosynthesis ( Figure 1 ) [ 7 , 8 , 9 , 10 , 11 ].…”