Malaria, the most prevalent parasitic disease, is considered a neglected disease owing to insufficient research and development in synthesis and therapy worldwide. Therapy failures are frequent and are due to a variety of factors such as the intrinsic characteristics of the disease, conditions of transmission, and the difficult control of spreading through tropical areas. Primary factors are the complexity of the parasite life cycle and the development of drug resistance. Another critical factor is the increasing number of immune-compromised patients that suffer from malaria and human immunodeficiency virus (HIV) co-infections. Most of the drugs currently available to treat malaria are quinoline derivatives modelled on the quinine molecule, found in the bark of Cinchona trees. Over the last 50 years the use of quinine has declined owing to the development of synthetic 4-aminoquinolines such as chloroquine. However, the malaria parasite is rapidly becoming resistant to the drugs currently available. Recently bisquinoline compounds were found more potent than chloroquine against both chloroquine-sensitive and resistant strains of malaria; this improved efficacy and prompted an increased interest in the design of these anti-malarial drugs. Although several synthetic methods are available to synthesise bisquinolines, we report the synthesis of bisquinolines from simple, readily available and cost- effective starting compounds. The synthesis was accomplished in four reaction steps using the Claisen condensation, Vilsmeir-Haack reaction, formation of a Schiff base and thermal cyclization, sequentially. We used a conventional energy source and microwave irradiation for the synthesis, wherever possible, of 2, 4-dichloro-3, 4'-biquinoline and 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline. In the first step, 3-acyl-2, 4-dihydroxyquinoline is synthesised from an equimolar mixture of methyl-2-aminobenzoate and ethyl acetoacetate by microwave irradiation for 3 minutes; the yield is 90 % whereas by 6 hours refluxing the yield is 75 %. This is followed by the synthesis of 3-chloro-3-(2,4-dichloroquinolin-3yl) acrylaldehyde, by combining DMF and POCl3 at 00C to form the electrophile which reacts with 3-acyl-2,4-dihydroxyquinoline under microwave irradiation for 5 minutes; the yield is 65 % whereas by 6 hours refluxing the yield is 50 %. In the next step, several protocols to prepare a Schiff base 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene aniline are investigated with the best yield of 75% obtained by microwave irradiation for 5 minutes. Subsequently three aniline derivatives viz, 4-methoxyaniline, 4-chloroaniline and 4-methylaniline, are used as substrate to prepare 3-chloro-3-(2,4-dichloroquinolin-3-yl) allylidene-4-methoxyaniline, 3-chloro-3-(2 ,4-dichloroquinolin-3-yl) allylidene-4-methylaniline and 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene-4-chloro aniline at 68, 78 and 64 % yield, respectively. In the final step, 2, 4-dichloro-3, 4'-biquinoline is prepared; several methods were investigated, however, the best yield is 24 % which is obtained under alkaline conditions in the presence of K2CO3 and DMF by microwave irradiation for 10 minutes. The 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline derivative is also prepared in 18 % yield under the same alkaline conditions. The outline of the total synthesis of bisquinoline is presented graphically below.
Assessing and Comparing COVID-19 Intervention Strategies Using a Varying Partial Consensus Fuzzy Collaborative Intelligence Approach
