Adsorption to the Surface of Hemozoin Crystals: Structure‐Based Design and Synthesis of Amino‐Phenoxazine β‐Hematin Inhibitors

• Published in: ChemMedChem Vol. 17; no. 10; pp. e202200139 - n/a
• Main Authors: Olivier, Tania, Loots, Leigh, Kok, Michélle, Villiers, Marianne, Reader, Janette, Birkholtz, Lyn‐Marié, Arnott, Gareth E., Villiers, Katherine A.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 18.05.2022; Wiley Subscription Services, Inc
• Subjects: Adsorption; Antimalarials; Binding sites; Chemistry, Medicinal; crystal growth; Crystal structure; Crystals; Diamines; Hemeproteins - chemistry; Hemozoin; heterocycles; Inhibitors; Life Sciences & Biomedicine; Pentane; Pharmacology & Pharmacy; phenoxazines; pi interactions; Plasmodium falciparum; Quinoline; Science & Technology; β-hematin; VITRO; CRYSTALLIZATION; inhibitors; adsorption; phenoxazines; HAEMOZOIN; DIGESTIVE VACUOLE; pi interactions; ANTIMALARIAL; QUINOLINE; MALARIA PIGMENT; HEME; heterocycles; PLASMODIUM-FALCIPARUM; crystal growth; beta-hematin; IN-VIVO CHARACTERIZATION; β-hematin
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202200139

In silico adsorption of eight antimalarials that inhibit β‐hematin (synthetic hemozoin) formation identified a primary binding site on the (001) face, which accommodates inhibitors via formation of predominantly π‐π interactions. A good correlation (r2=0.64, P=0.017) between adsorption energies and the logarithm of β‐hematin inhibitory activity was found for this face. Of 53 monocyclic, bicyclic and tricyclic scaffolds, the latter yielded the most favorable adsorption energies. Five new amino‐phenoxazine compounds were pursued as β‐hematin inhibitors based on adsorption behaviour. The 2‐substituted phenoxazines show good to moderate β‐hematin inhibitory activity (<100 μM) and Plasmodium falciparum blood stage activity against the 3D7 strain. N1,N1‐diethyl‐N4‐(10H‐phenoxazin‐2‐yl)pentane‐1,4‐diamine (P2a) is the most promising hit with IC50 values of 4.7±0.6 and 0.64±0.05 μM, respectively. Adsorption energies are predictive of β‐hematin inhibitory activity, and thus the in silico approach is a beneficial tool for structure‐based development of new non‐quinoline inhibitors. The in silico adsorption of 53 cyclic scaffolds to the fastest‐growing (001) face of a β‐hematin crystal identified the phenoxazine scaffold for further derivatization. A small library of 2‐ and 3‐substituted amino‐phenoxazine compounds with predicted β‐hematin inhibitory activity were synthesized. P2a shows the most promising β‐hematin inhibition and antiplasmodium activity.