Roy et al : Synthesis and In vitro Antimalarial Activity of Some New 4-Aminoquinoline Mannich Base Derivatives 803 ew 4-(substituted)-Pyrazolone. Part 2: Antifungal Activity of Synthesis and In vitro Antimalarial Activity of Some New 4-Aminoquinoline Mannich Base Derivatives S. Roy 1* , D. Chetia 2 , M. Rudrapal 3 and A. Prakash 4 1 Fresenius Kabi Oncology Ltd., Kalyani, Nadia, West Bengal, India. 2 Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India. 3 Aditya Institute of Pharmaceutical Sciences and Research, Surampalem, E. G. Dist., A. P., India. 4 Regional Medical Research Centre, I C M R, N E Region, Dibrugarh, Assam, India. ABSTRACT: A new series of 4-aminoquinoline Mannich base derivatives were prepared by selectively modifying the aliphatic diethyl amino function of isoquinewith different aliphatic/aromatic heterocyclic primary amino moieties at Mannich side chain. The synthesized compounds were characterized by their physical,analytical and spectral data, and screened for in vitro antimalarial activity against a chloroquine-sensitive 3D7 strain of Plasmodium falciparum. All the compounds showed in vitro antimalarial activity at the tested dose; which, however, was considerably less than that of the standard reference drug, chloroquine. Among the synthesized compounds, compounds with cyclohexyl (2f), methyl (2c) substitutions showed comparatively better activity than other compounds with n-octyl (2a), propyl (2b), 3-aminopropyl (2d) and furan-2-ylmethyl (2e) substitutions at aminomethyl side chain. The results clearly demonstrate that compound with saturated cycloalkylmoiety (cyclohexyl) exhibitedto some extentmore activity as compared to the compound with heterocyclicmoiety (furan-2-ylmethyl); and compounds with short chain alkyl substitutions (methyl, propyl etc.) were found to be more potent than that of compounds with long chain alkyl substitution (n-octyl). KEYWORDS: 4-Aminoquinoline; Isoquine; Mannich base; Antimalarial; Plasmodium falciparum; alkyl chain. Introduction Malaria is a life-threatening infectious disease caused by protozoan parasites of the genus Plasmodium; P. falciparum, P. vivax, P. malariae, and P. ovaleare four well known species of human malaria parasite 1, 2 and more recently another species, P. knowlesi has been documented 3 . It is one of the most widespread diseases worldwide particularly in tropical and subtropical regions; both from the point of view of mortality and morbidity 4,5 . Since past few decades, 4-aminoquinoline drugsespecially chloroquine (CQ) arein use for the treatment of malaria; but rapid development and spread of resistance of malaria parasite, especially P. falciparum towards CQ has limited their use in the treatment of malaria 6 . Amodiaquine(AQ), a 4-aminoquinoline Mannich base derivative has been introducedthereafter and was found effective against many CQ-resistant strains of P. falciparum; but clinical use of AQ has severely restricted because of having hepatotoxicity and agranulocytosis like severe side effects 7,8 . Further studies on amodiaquine structural analoques 9 have led to the development novel amodiaquineregioisomer, isoquine (IQ), which was found to be more effective than AQ and devoid of any severe side effects. However, structure activity relationship studies on 4-aminoquinoline antimalarial compounds suggested that 7-chloro-4-aminoquinoline nucleus is obligatory for antimalarial activity 10 and recent literature on amodiaquine structural analogues has reported that the presence of 4´ hydroxyl group within the aromatic ring imparts greater inherent antimalarial activity against chloroquine-resistant parasite. Moreover, interchange of the hydroxyl group and the Mannich side chain as in isoquine prevents oxidation to toxic metabolites while retaining desirable activity profile 9 . Based on this fact, we presumed to designing 4- aminoquinoline Mannich bases by selectively modifying the side chain amino group with primary aminesthat could improve the antimalarial activity and might be effective against resistant parasites. In the current work, some new derivatives of 4-aminoquinoline Mannich bases were synthesized and screened for in vitro antimalarial activity. Experimental All the chemicals were of synthetic grade and commercially procured from Sigma-Aldrich Corporation (USA), Merck (Germany) or Spectrochem Pvt. Ltd. (India). 4,7-dichloroquinoline was obtained as gift sample from M/s. Mangalam Drug & Organics, Mumbai, India. Melting points of the synthesized compounds were determined in open capillaries on a Veego-MPI melting point apparatus International Journal of Drug Design and Discovery Volume 3 • Issue 2 • April – June 2012. 803-808 * For correspondence: S. Roy, Email: roy.susanta84@gmail.com 803