Spectroscopic Manifestations Of (Anti)Aromaticity In Oxidized And Reduced Porphyrin And Norcorrole.

Aromaticity and antiaromaticity are foundational principes in organic chemistry, regularly invoked to explain stability, structure, and magnetic and electronic properties. There are ongoing challenges in assigning molecules as aromatic or antiaromatic using optical spectroscopy. Here we report spectroelectrochemical and computational analyses of porphyrin (18π neutral, aromatic) and norcorrole (16π neutral, antiaromatic), and their oxidized (16π porphyrin dication) and reduced (norcorrole 18π dianion) forms. Our results show that while the visible spectra are characteristic of (anti)aromaticity consistent with Hückel's rules, the IR spectra are much less informative, owing to the relative rigidity of norcorrole. The results have implications for the assignment of (anti)aromaticity in both ground-state and time-resolved excited-state spectra.

Fragment-based drug discovery for disorders of the central nervous system: designing better drugs piece by piece.

Fragment-based drug discovery (FBDD) has emerged as a powerful strategy to confront the challenges faced by conventional drug development approaches, particularly in the context of central nervous system (CNS) disorders. FBDD involves the screening of libraries that comprise thousands of small molecular fragments, each no greater than 300 Da in size. Unlike the generally larger molecules from high-throughput screening that limit customisation, fragments offer a more strategic starting point. These fragments are inherently compact, providing a strong foundation with good binding affinity for the development of drug candidates. The minimal elaboration required to transition the hit into a drug-like molecule is not only accelerated, but also it allows for precise modifications to enhance both their activity and pharmacokinetic properties. This shift towards a fragment-centric approach has seen commercial success and holds considerable promise in the continued streamlining of the drug discovery and development process. In this review, we highlight how FBDD can be integrated into the CNS drug discovery process to enhance the exploration of a target. Furthermore, we provide recent examples where FBDD has been an integral component in CNS drug discovery programs, enabling the improvement of pharmacokinetic properties that have previously proven challenging. The FBDD optimisation process provides a systematic approach to explore this vast chemical space, facilitating the discovery and design of compounds piece by piece that are capable of modulating crucial CNS targets.