Synthesis And Biological Activity Of Novel Quinoline And Quinoxaline Derivatives

As well known,N-heterocyclic compounds have significant potential for the development of novel and effective therapeutic agents.Especially,quinoline-and quinoxaline-containing heterocycles are very important structural moieties present in numerous pharmacologically active natural products and synthetic compounds associated with a wide spectrum of biological activities.Due to their striking biological activities,considerable synthetic efforts have been devoted surrounding the quinoline and quinoxaline rings for further structural diversity and functionalization by both organic and medicinal chemists with the aim of enhancing the potency of this class of compounds.In this thesis,we utilized the newly-synthesized diethyl 2-(bromomethyl)quinoline-3,4-dicarboxylate and ethyl3-(bromomethyl)quinoxaline-2-carboxylate as the substrates to conduct the reaction with various substituted salicylaldehydes,phenols and heteroaromatic aldehydes,giving rise to 42 structurally novel and intriguing quinoline and quinoxaline derivatives.Their structures were confirmed by IR,1H NMR,13 C NMR and HRMS.Further,a preliminary evaluation for their in vitro antibacterial and anti-tumor activities was was assayed,and some of them exhibited promising inhibitory activity.The research work mainly contains four parts as follows.In the first part,a recent advance on the biological and pharmacological activities of quinoline and quinoxaline derivatives has been reviewed through the survey of related literature.In the second part,diethyl 2-(bromomethyl)quinoline-3,4-dicarboxylate was synthesized and applied as substrate in the one-pot sequential Rap-Stoermer type reaction with various substituted salicylaldehydes followed by ester hydrolysis reaction using anhydrous K2CO3 as base and PEG-400 as catalyst.Through the convenient and effective one-pot two-step procedure,a series of hitherto unreported 2-(2-benzofuryl)-3,4-quinoline dicarboxylic acid derivatives 4a-4j weresuccessfully obtained in good yield of 66.1%-70.8%.In the third part,we further investigate the reactivity of diethyl2-(bromomethyl)quinoline-3,4-dicarboxylate in the one-pot sequential Williamson reaction with various substituted phenols followed by ester hydrolysis reaction under similar reaction conditions,affording a series of new type of2-aryloxymethyl-3,4-quinoline dicarboxylic acid derivatives 6a-6o in good yields ranging 75.1%-81.2%.A primary evaluation for their inhibitory activity against Mycobacterium tuberculosis Leucyl-tRNA synthetase(Mtb LeuRS)was carried out,and the test results revealed that this class of compounds showed moderate to good inhibitory effects against M.tuberculosis LeuRS,among which compound 6k exhibited the best activity with the inhibition value reaching to 83.49%.In the fourth part,by utilizing the newly-synthesized ethyl3-(bromomethyl)quinoxaline-2-carboxylate as substrate,we accomplished a simple and facile synthesis of a new series of derivatives of vinylene-linked bis-heterocycles,namely 2-indolyvinylquinoxaline-3-carboxylic acids 8a-8g and2-quinolinevinylquinoxaline-3-carboxylic acids 10a-10 j in 60.1%-71.6% yields through one-pot sequential Arbuzov/Horner-Wadsworth-Emmons(HWE)/ester hydrolysis reaction procedure.A primary evaluation for their in vitro antitubercular activity against Mycobacterium tuberculosis Leucyl-tRNA synthetase(Mtb LeuRS)and anti-tumor activity against A549 and HT29 was carried out.The results showed that this class of compounds showed potential activity against Mtb LeuRS,among which 8d had the highest activity with an inhibition rate of 85.85%.But they exhibited poor anti-tumor activity against A549 and HT29.