Investigation Into Novel Mukanadin B, Mukanadin D and Mukanadin F Derivatives as Antagonists of 5‐HT1A Signalling

• Published in: ChemMedChem Vol. 19; no. 15; pp. e202400102 - n/a
• Main Authors: Rees, Shaun W. P., Rees, Tayla A., Rensburg, Michelle, Walker, Christopher S., Pilkington, Lisa I., Barker, David
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.08.2024; Wiley Subscription Services, Inc
• Subjects: Antagonists; Chemical synthesis; Chemistry, Medicinal; Hydantoin; Life Sciences & Biomedicine; Marine biology; Medicinal chemistry – Keyword catalogue; Mukanadin; Natural products; Natural products – Keyword catalogue; Neurotransmitters – Keyword catalogue; Pharmacology & Pharmacy; Science & Technology; Serotonin; Mukanadin; INHIBITION; Serotonin; BROMOPYRROLE ALKALOIDS; HYMENIDIN; Neurotransmitters - Keyword catalogue; OROIDIN; Natural products - Keyword catalogue; SEROTONERGIC RECEPTORS; Medicinal chemistry - Keyword catalogue; Medicinal Chemistry; Natural Products; Neurotransmitters
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202400102

Marine bromopyrrole alkaloids are a diverse family of natural products with a large array of biological applications. The mukanadin family is a group of molecules consisting of seven members (mukanadin A‐G) that possess a range of biological activities. Inhibition of serotonergic signaling has been demonstrated by mukanadin B derivatives, presenting this chemical scaffold as a candidate for further SAR exploration. A library of thirteen novel mukanadin B and D derivatives with structural variation targeted at the pyrrole ring, central linker and hydantoin ring, were synthesized. These analogues were subsequently assessed for serotonergic antagonism, in addition to natural products, mukanadin B, D, F and 9‐hydroxy mukanadin B. A collection of compounds exhibited significant 5‐HT1A signaling, including five of the novel derivatives and two of the naturally occurring bromopyrroles, mukanadin B and F. Particular SAR information could be determined from these results, such as modification of the pyrrole ring being a well‐tolerated strategy for improving serotonergic inhibition. Other changes to the pharmacophore led to significant reduction in activity such as saturation of the linker region, or no conclusive improvement in inhibitory activity such as a 9‐OH group or replacement of the hydantoin ring with a triazole moiety. The mukanadin family of bromopyrrole alkaloids have been associated with antagonism of serotonin signalling. Thirteen novel mukanadin B and D analogues were synthesized and assessed for 5‐HT1A inhibition in order to further explore this pharmacophore. Multiple novel derivatives induced significant 5‐HT1A inhibition, at levels similar to naturally occurring mukanadin B.