Design, synthesis, and biological evaluation of novel oxadiazole- and thiazole-based histamine H3R ligands

Abstract

Histamine H₃ receptor (H₃R) is largely expressed in the CNS and modulation of the H₃R function can affect histamine synthesis and liberation, and modulate the release of many other neurotransmitters. Targeting H₃R with antagonists/inverse agonists may have therapeutic applications in neurodegenerative disorders, gastrointestinal and inflammatory diseases. This prompted us to design and synthesize azole-based H₃R ligands, i.e. having oxadiazole- or thiazole-based core structures. While ligands of oxadiazole scaffold were almost inactive, thiazole-based ligands were very potent and several exhibited binding affinities in a nanomolar concentration range. Ligands combining 4-cyanophenyl moiety as arbitrary region, para-xylene or piperidine carbamoyl linkers, and/or pyrrolidine or piperidine basic heads were found to be the most active within this series of thiazole-based H₃R ligands. The most active ligands were in silico screened for ADMET properties and drug-likeness. They fulfilled Lipinski's and Veber's rules and exhibited potential activities for oral administration, blood-brain barrier penetration, low hepatotoxicity, combined with an overall good toxicity profile.

Keywords: ADMET; H(3) receptor; Histamine; Ligands; Oxadiazole; Thiazole.