Synthesis and Antimicrobial Activity of 3-Cyano-4-imino-9-methoxy-4 H-pyrimido [ 2 , 1-b ] pyrimido [ 4 , 5b ] quinoline and 2-Substituted Derivatives

e 2-amino-7-methoxypyrimido[4,5-b]quinoline (1) on treatment with bis(methylthio)methylenemalononitrile (2) in ethyl alcohol and catalytic amount of TEA gives 3-cyano-4-imino-9-methoxy-2-methythio-4H-pyrimido[2,1-b]pyrimido[4,5-b]quinoline (3).e latter were further reacted with selectedN-, O-, andC-nucleophiles such as aryl amines, hetryl amines, substituted phenols, and compounds containing an active methylene group.


Introduction
Quinoline derivatives represent the major class of heterocycles and a number of preparations have been known since the late 1800s.e quinoline ring system occurs in various natural products, especially in alkaloids.e quinoline skeleton is oen used for the design of many synthetic compounds with diverse pharmacological properties.In 1820, quinine was isolated as the active ingredient from the bark of cinchona tree and successively replaced the crude bark for the treatment of malaria.Despite its relatively low efficacy and tolerability, quinine still plays an important role in the treatment of multiresistant malaria.is molecule has also played a historical role in organic chemistry as a target for structural determination and total synthesis [1] and recently both stereoselective [2] and enantioselective [3] total syntheses.Quinoline and its derivatives are receiving important due to their wide range of biological activities as a drug analgesics [4], antiamoebic [5][6][7][8], trypanocidal [9], antiseptic [10], and antiserotonin [11].In addition to these, derivatives also exhibit good antimalarial [12,13], antitubercular [14], antibacterial [15], antihistaminic [16], anti-neurodegerneative [17], anticonvulsant [18], antitumor [19], anticancers [20,21], and antiallergics [22] activities.
In the light of these valid observations, such fused quinoline with pyrimidine ring would exhibit some interesting pharmacological activities; further, the ring anellation to amino groups containing nitrogen heterocycles with ketene dithioacetals as reagent has been reported [23][24][25].Recently, we report one pot synthesis of 3-cyano-9-methyl-2-methylthio-4-oxo-4H-pyrimido [2,1-b] pyrimido [4,5-b] quinoline and its reaction with selected nucleophiles [26].In continuation, this remains an opportunity for further development of milder condition with better yields.e compound 3 was prepared by the reaction of 2-amino-7-methoxy pyrimido [4,5-b] quinolone 1 with bis(methylyhio)methylene malononitrile 2 in presence of ethyl alcohol and catalytic amount of TEA, Scheme 1.A plausible mechanism for the formation of parent compound 3 can be adduced as shown in Scheme 2. Compound 3 possesses an active methylthio group at the 2 positation that is activated by the ring 1-nitrogen atom and the electron withdrawing 3-cyano group.Compound 3 was reacted with selected N-, O-, and C-nucleophiles like aryl amines, substituted phenols, heteryl amines, and compound containing active methylene group.Hence, compound 3 independently reaction with different substituted anilines, substituted phenols, active methylene compounds, and hetryl amines in presence of ethyl alcohol and catalytic amount of TEA afforded new compounds 4a-e, 5a-f, 6a-6d, 7a-7d, and Scheme 3.

Experimental Section
Melting points were determined by an open capillary method and are uncorrected.e chemicals and solvents were used for laboratory grade and were puri�ed.IR spectra were recorded (in KBr pallets) on Shimadzu spectrophotometer.
1 HNMR spectra were recorded (in DMSO-d 6 ) on Avance-300 MHz spectrometer using TMS as an internal standard.e mass were recorded on EI-Shimadzu GC-MS spectrometer.Elemental analyses were performed on a Heraeus CHN-O rapid analyzer.

Conclusion
In this communication all synthesized compounds reported �rst time and describe the simple route of their synthesis in mild condition with good yield.e present study showed that all the title compounds were exhibiting signi�cant antibacterial and antifungal activities.However, further studies are required to establish the mechanism of action of the title compounds.From the screening data, it was found that 4c, 4e, 5d, 5e, 6b, and 7d derivative have encouraging antibacterial and antifungal activity, which needs to be further investigated to get better antibacterial and antifungal agents.