ABSTRACT
A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.
Subject(s)
Alkaloids/pharmacology , DNA Topoisomerases, Type I/metabolism , Drug Design , Pyrroles/pharmacology , Quinones/pharmacology , Topoisomerase I Inhibitors/pharmacology , Alkaloids/chemical synthesis , Alkaloids/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Quinones/chemical synthesis , Quinones/chemistry , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/chemistryABSTRACT
Synthesis of novel 4(3H)-quinazolinonyl aminopyrimidine derivatives has been achieved via quinazolinonyl enones which in turn were obtained from 2-acyl-4(3H)-quinazolinone. They have been assayed for biofilm inhibition against Gram-positive (methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative bacteria (Acinetobacter baumannii). The analogues with 2,4,6-trimethoxy phenyl, 4-methylthio phenyl, and 3-bromo phenyl substituents (5h, 5j & 5k) have been shown to inhibit biofilm formation efficiently in MRSA with IC50 values of 20.7-22.4 µM). The analogues 5h and 5j have demonstrated low toxicity in human cells in vitro and can be investigated further as leads.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Pyrimidines/pharmacology , Quinazolinones/pharmacology , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/physiology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/toxicity , Cell Line , Humans , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/physiology , Microbial Sensitivity Tests , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/toxicity , Quinazolinones/chemical synthesis , Quinazolinones/toxicity , Structure-Activity RelationshipABSTRACT
A facile synthesis of C-ring substituted luotonins and vasicinones has been realized via a super-acid-mediated aza-Nazarov cyclization of quinazolinonyl enones. The regioselectivity of the cyclization is highly dependent on proton availability in the reaction medium.
