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Please cite this article as: R. Raj, P. Singh, P. Singh, J. Gut, P.J. Rosenthal, V. Kumar, Azidealkyne cycloaddition en route to 1H-1,2,3-Triazole-tethered 7-chloroquinoline-isatin chimeras: Synthesis and antimalarial evaluation, European Journal of Medicinal Chemistry (2013), doi: 10.1016/ j.ejmech.2013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTAzide-alkyne cycloaddition en route to 1H-1,2,3-Triazole-tethered The compound 8h with an optimum combination of longer alkyl chain length and chloro substitutent at C-5 position of isatin ring displayed the best activity among the test compounds. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Abstract:We describe the synthesis and antimalarial activities of 1H-1,2,3-triazole tethered 7-chloroquinolineisatin hybrids. Activity against cultured parasites was dependent on the C-5 substituent of the isatin ring as well as the alkyl chain length between the isatin and 7-chloroquinoline moieties. Compound 8h, with an optimum alkyl chain length (n=3) and a chloro substitutent at the C-5 position of the isatin ring, displayed the best activity among the test compounds, with IC 50 value of 1.21 µM against cultured W2-strain Plasmodium falciparum.

A series of twenty piperazine-tethered 7-chloroquinoline-isatin hybrids have been synthesized via either direct nucleophilic substitution or Cu(Ι)Cl-mediated Mannich reaction. These new conjugates were evaluated for their antimalarial and antitubercular efficacy against a chloroquine-resistant strain of Plasmodium falciparum and Mycobacterium tuberculosis, respectively, while the cytotoxic profiles were evaluated against 3T6 cell line, a permanent mouse embryonic fibroblast cell line. The most potent of the test compound with IC50 of 0.22 μm against W2 strain of P. falciparum and 31.62 μm against the embryonic fibroblast cell line (cytotoxicity) displayed a high selective index of 143.73.

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