Microwave assisted synthesis of piperazine and morpholine substituted quinoline derivatives

There has been tremendous interest in developing efficient methods for the synthesis of quinoline derivatives with significant applications in the fields of medicinal, bioorganic, industrial and synthetic organic chemistry. However, due to the lack of availability of suitable procedures for the preparation of poly bromination/substitution of quinoline core, this area still remains unlaboured. The work presented describes convenient approaches and strategy towards the synthesis of morpholine and piperazine derivatives of quinoline. 1,2,3,4-tetrahydroquinoline (THQ, 11) was brominated to furnish 6-bromtetrahydroquinoline (6-BrTHQ, 12) and 6,8-diBrTHQ (13) followed by their aromatization to bromo quinoline analogues. In addition these, 6,8-diBrTHQ (13) was further brominated to 3,6,8-tribromoquinoline (3,6,8-triBrQ, 15). The synthesized derivatives were subjected to nitration. It was observed that Br-quinolines at C-5 and Quinoline- N-oxides nitrate at C-4 and C-5. The reactivity difference of bromine atoms on the heterocyclic ring, facilitates the consective substitution. Additionally, –NO2 substituted bromo derivatives are the potential precursors for poly derivatization of quinoline. 6-bromo (14) and 3,6,8-tribromoquinolines (15) were transformed to corresponding 5-NO2 quinolines by direct nitration reactions. 5-nitro-6-bromoquinoline (17) was converted to corrosponding morpholine and piperazine derivatives of quinoline by microwave-assisted nucleophilic substitution while 5-nitro-3,6,8-tribromoquinoline (18) regioselectively (at C-6 and C-8 positions) reacted with morpholine/piperazine in condition of classical heating method. However, microwave assisted reaction of 3,6,8-tribromoquinoline (15) with morpholine and piperazine exhibited different regioselectivity (at C-3 position) The newly synthesized quinoline compounds were tested in vitro for their their biological activities such as anticancer, cytotoxic and antimetastatic activities by using BrDU cell proliferation assay, Lactate Dehydrogenase assay respectively. In addition, mode of action of novel biologically active compounds with anticancer activity was determined by using molecular methods such as DNA laddering for apoptosis and Topoisomerase inhibition assays. 6,8-dibromo-3-morfonililquinoline (26) and 6,8-dibromo-3-piperazinililquinoline (25) compounds showed a higher inhibition of the cells tested only against C6 cancer cells compared to 5-FU. 6,8-dibromo-3-piperazinyl quinoline (25) has a higher potential to be more effective anti-cancer agent than 6,8-dibromo-3-morfonililquinoline (26).