Use of Intramolecular 1,5-Sulfur–Oxygen and 1,5-Sulfur–Halogen Interactions in the Design of N-Methyl-5-aryl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine SMN2 Splicing Modulators

Abstract

Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. Branaplam (1) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur–oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26, which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington’s Disease

“…The SMN2 compounds 1 and 2 both assume a planar structure in the core region as necessitated by the bicyclic core present in 1 and by the intramolecular hydrogen bonding (HB) interaction in 2 . − Similar conformational preference is presumably operating in the fluorinated benzamide core of 3 where an intramolecular HB (F---HN) locks the aryl amide in a plane . Whether the ortho -F-amide group in 3 was near optimal for the targeted HTT activity was unclear at the onset.…”

“…5-Chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (102A, 70 mg, 0.23 mmol), (S)-N-methylpyrrolidin-3-amine (23 mg, 0.23 mmol), cesium carbonate (325 mg, 1 mmol), and DMF (2 mL) were combined in a sealed tube and heated to 100 °C for 16 h. The reaction mixture was cooled to rt, cesium salts (22). 5-Chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (102A, 127 mg, 0.415 mmol), cesium carbonate (271 mg, 0.831 mmol), (R)-3-(boc-amino)pyrrolidine (77 mg, 0.415 mmol), and 1,4-dioxane (15 mL) were combined in a sealed tube and heated to 100 °C for 4 h. The reaction mixture was cooled to rt.…”

Electronic effect‐dependent intramolecular non‐covalent interactions on the activity of 4,4‐dimethylimidazolidin‐2‐one pharmacophore‐based androgen receptor antagonists

“…As a result of this increased flexibility, the majority of compounds in the series show good anti‐PC activity. Very interestingly, for the first time we found that electronic effect of the substituent plays a major role on the activity compounds; it means that the electronic effect of the substituents influences the strength of the non‐covalent interactions, which influences the free rotation of the benzene ring with respect to the pharmacophore, resulting in change of activity (Axford et al, 2021). Furthermore, the synthesized compounds lack any sort of amide functional group, which is a key functional group for both first and second‐generation approved drugs.…”

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

“…More recently, the central benzene ring in the symmetrically disposed diprivomicin 120a has been found to be recalcitrant to replacement with the more conventional isosteres cyclohexane ( 120b , 120c ), acetylene ( 120d ), ethylene ( 120e ), and thiophene ( 120f ), with only pyridine ( 120g ) being effective among the motifs examined, although the survey conducted was restricted in scope . Indeed, there are a number of drug pharmacophores and binding sites that demand planarity, reflecting a need for the design of new phenyl ring mimics that can capture key aspects of drug–target interactions or scaffolding functions while abrogating some of the developability liabilities associated with a benzenoid ring. − …”