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Crystal structure of the potent bisquinoline antimalarial agent (±)-trans-N 1,N 2-bis(7-chloroquinolin-4-yl) cyclohexane-1,2-diamine dimethanesulfonate salt hydrate in relation to its biological properties

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Abstract

The neighboring 4-aminoquinoline substituents of the bisquinoline (±)-trans-N 1,N 2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine dimethanesulfonate salt crystallized in the diequatorial position which is in agreement with quantum chemical calculations. The bisquinoline salt crystallized in the monoclinic C2/c space group with a = 19.328(4) Å, b = 15.618(3) Å, c = 20.382(4) Å, β = 98.84(3)°. The two quinoline nitrogen atoms are protonated by the salt as predicted by calculated electrostatic surface potentials. The −5 kcal/mol isopotential surface of the bisquinoline resembles that of chloroquine, which may explain the potent inhibition of hematin polymerization by both the bisquinoline and chloroquine. The smaller HOMO/LUMO gap of the bisquinoline is consistent with its phototoxicity. The overall conformation, the ability of all nitrogen atoms to participate in hydrogen bonding, and the electrostatic interaction of the quinoline rings in the crystal packing may all aid in the determination of the binding pharmacophore of the bisquinoline.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, Maryland, 20910-7500

    Jean M. Karle & Apurba K. Bhattacharjee

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska

    Jonathan L. Vennerstrom

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  1. Jean M. Karle
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  2. Apurba K. Bhattacharjee
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  3. Jonathan L. Vennerstrom
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Correspondence to Jean M. Karle.

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Karle, J.M., Bhattacharjee, A.K. & Vennerstrom, J.L. Crystal structure of the potent bisquinoline antimalarial agent (±)-trans-N 1,N 2-bis(7-chloroquinolin-4-yl) cyclohexane-1,2-diamine dimethanesulfonate salt hydrate in relation to its biological properties. Journal of Chemical Crystallography 32, 133–139 (2002). https://doi.org/10.1023/A:1015602002694

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