ABSTRACT
Development of a chiral pool-based synthesis of 10b-aza-analogues of biologically active Amaryllidaceae alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10b-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.
ABSTRACT
The discovery of two quinazolinones with selective, single-digit micromolar activity (IC50â¯=â¯6-7⯵M) against the tachyzoites of the apicomplexan parasite Toxoplasma gondii is reported. These potent and selective third generation derivatives contain a benzyloxybenzyl substituent at C2 and a bulky aliphatic moiety at N3. Here we show that these quinazolinones inhibit T. gondii tachyzoite replication in an established infection, but do not significantly affect host cell invasion by the tachyzoites.
Subject(s)
Antiprotozoal Agents/pharmacology , Quinazolinones/pharmacology , Toxoplasma/drug effects , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Fibroblasts/drug effects , Humans , Molecular Structure , Parasitic Sensitivity Tests , Quinazolinones/chemical synthesis , Quinazolinones/chemistry , Skin/cytology , Skin/drug effects , Structure-Activity RelationshipABSTRACT
The discovery of antiviral activity of 2,3-disubstituted quinazolinones, prepared by a one-pot, three-component condensation of isatoic anhydride with amines and aldehydes, against Herpes Simplex Virus (HSV)-1 is reported. Sequential iterative synthesis/antiviral assessment allowed structure-activity relationship (SAR) generation revealing synergistic structural features required for potent anti-HSV-1 activity. The most potent derivatives show greater efficacy than acyclovir against acute HSV-1 infections in neurons and minimal toxicity to the host.
