Density functional calculations of the structural, thermodynamic & spectroscopic properties of spiroindolone

Fred L. Nesbitt & Rose A. NesbittNETA International,Seabrook, MD USA

Introduction

• Spiroindolone has been shown to be effective against two species of malaria (Plasmodium falciparum and Plasmodium berghei)• 40% of the global population affected• Plasmodium falciparum - most virulent and

affects about half a billion people per year • A million deaths in 2008, 90% of these are

children• Most current effective drug is Artemisinin

combination therapies (ACT) shows resistance hence the need for a new drug

All geometries were computed using the B3LYP densityfunctional theory method using Spartan 10

Geometries optimized were performed using the 6-31G*basis set

Computational Method

Lewis structure of SpiroindoloneC19H14ClF2N3O

RESULTSStructure of Spiroindolone

RESULTSSpace filling model of Spiroindolone

RESULTSThermodynamic properties

∆fH0 =843 kJ/Mole

S0 =638 J/Mole K

∆fG0 = 654 kJ/Mole

Cp0 = 352 J/Mole K

RESULTSDipole moment

Dipole Moment = 5.37 Debye

RESULTSInfrared spectra

RESULTSRAMAN spectra

RESULTSNMR spectra

RESULTSUV-Vis spectra

RESULTSDensity potential map

RESULTSHOMO Surface

RESULTSLUMO Surface

RESULTSElectrostatic Potential

Future Studies

Perform density functional calculations on the three other enantiomers of spiroindolone To determine the following properties IR spectra, NMR spectra, dipole moment and thermodynamic properties. These properties will be important in eliminating impurities (the other 3 enantiomers) of spiroindolone which may be responsible for side effects.

References

1.Bryan K.S. Yeung, et.al. Spirotetrahydro β-carolines (Spirindolones): A new class of potent and orally efficacious compounds for the treatment of malaria.,J.Med. Chem., 2010, 53, 1555 – 1564. 2.SPARTAN '08, build 131 (Jan 29 2009)Wavefunction Developers: B.J. Deppmeier, A.J. Driessen, T.S. Hehre, W.J. Hehre, J.A. Johnson, P.E. Klunzinger, J.M. Leonard, I.N. Pham W.J. Pietro, Jianguo Yu Q-Chem Developers: Y. Shao, L. Fusti-Molnar, Y. Jung, J. Kussmann, C. Ochsenfeld,S. T. Brown, A. T. B. Gilbert, L. V. Slipchenko, et. al., Wavefunction Inc.