MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2002; 40: 477–479
Spectral Assignments and Reference Data
1H and 13C NMR spectral characterization of
some antimalarial in vitro 2,4-diamino-10-
methylpyrimido[4,5-b]-5-quinolone
derivatives
Compound
R
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
7-OMe
8-OMe
9-OMe
7,8-OMe
7,9-OMe
7-Me
8-Me
7-Cl
8-Cl
N
O
6
9
4
N
R
N
N 1
NH2
1
Jaime E. Charris,1∗ Jose N. Domınguez, Neira Gamboa,2
´
´
CH3
1-13
Jorge Angel,3 Nolberto Pina, Mayamaru´ Guerra,3
3
˜
4
Elba Michelena3 and Simon E. Lopez
´
´
6,7-Cl
7,8-Cl
7-F
1
Laboratorio de S´ıntesis Orga´ nica, Universidad Central de Venezuela,
Aptdo. 47206, Los Chaguaramos 1041-A, Caracas, Venezuela
2
Departamento de Biolog´ıa, Facultad de Farmacia, Universidad Central
Scheme 1. Structures of 2,4-diamino-10-methylpyrimido[4,5-b]-5-qu-
inolones 1–13.
de Venezuela, Caracas, Venezuela
Escuela de Qu´ımica, Facultad Experimental de Ciencias, Universidad
3
del Zulia, Maracaibo, Venezuela
4
Departamento de Qu´ımica, Universidad Simo´ n Bol´ıvar, Caracas,
EXPERIMENTAL
Venezuela.
Compounds
The quinolones 1–4 were synthesized according to the literature6
and 5–13 were prepared by the synthetic route shown in Scheme 2.
The respective phenyl isothiocyanate was condensed with ethyl
cyanoacetate in potassium hydroxide, MeI and dry 1,4-dioxane,
the resulting N,S-acetals I were cyclized thermally and finally
the quinolones II were N-alkylated regiospecifically by heating
with potassium carbonate, DMF and MeI. The final products III
were obtained when II was reacted with guanidine sulfate and
anhydrous potassium carbonate in DMF. The structures and purities
of the compounds were confirmed by their melting-points, elemental
analyses (Atlantic Microlab Inc., Norcross, GA, USA) and IR (Table 1)
and NMR spectra.
Received 2 January 2002; accepted 28 January 2002
We report the 1H NMR and 13C NMR chemical
shifts and J(H,H), J(H,F) and J(C,F) coupling constants
of 13 2,4-diamino-10-methylpyrimido[4,5-b]-5-quinolone
derivatives, some of them with moderate activity against
Plasmodium falciparum in vitro. They were character-
ized and assigned on the basis of 1H, 13C and 13C–1H
(short- and long-range) correlated spectra. Copyright
2002 John Wiley & Sons, Ltd.
KEYWORDS: NMR; 1H NMR; 13C NMR; quinolones; antimalarials
NH2
N
O
O
CN
EtO2C CN
SMe
INTRODUCTION
R
R
N
CH3
N
N
CH3
N
SCH3
NH2
R
H
Malaria is a major public health problem, endemic in over 100
countries in the world. The World Health Organization (WHO)
estimates that there are 300 million clinical cases every year,
I
II
III
with over
1
million deaths.1 The emergence and spread of
Scheme 2. Preparation of compounds 5–13.
resistance to antimalarial drugs has highlighted the need for
the discovery and development of novel antimalarial molecules.
To achieve this goal, antimalarial drug research, on the one
hand, needs to focus on validated targets in order to generate
new drug candidates and, on the other hand, needs to identify
the targets for the future by studying the basic metabolic and
biochemical processes of the malaria parasite.2,3 Also, we have
recently reported the synthesis and spectral characterization of some
3-amino-9-phenylpyrazolo[3,4-b]-4-quinolones and 2,4-diamino-10-
phenylpyrimido-[4,5-b]-5-quinolones.4–7 These compounds proved
to be an interesting family of antimalarial agents in vitro. In view of
these findings, there has been renewed interest in our laboratories
in the synthesis, identification and spectral characterization of new
analogues bearing MeO, Cl and F substituents and a methyl group
at position 10. In this paper we present 1H NMR and 13C NMR data
for 2,4-diamino-10-methylpyrimido[4,5-b]-5-quinolone derivatives
(Scheme 1). They have demonstrated amoderate antimalarial activity
against a chloroquine-resistant strain of Plasmodium falciparum in vitro
(IC50 D ꢀ1–3 ð 10ꢀ6 M) and no activity against in vitro non-enzymatic
heme polymerization.
NMR spectroscopy
NMR spectra were recorded on a JEOL EX 270 Fourier transform (FT)
NMR spectrometer and Bruker AMX 500 FT (500 MHz) instrument
using DMSO-d6; tetramethylsilane was used as an internal standard.
The instrument were equipped with a 5 mm broadband probe head.
Processing was performed using the program DELTA V1.8, and
XWIN NMR V2.5, respectively, running on a Silicon Graphics
Workstation.
In 1H NMR experiments, the parameters were as follows: spectral
°
window, 15 ppm; width of 30 pulse, 2 µs; relaxation delay, 4 s; and
number of scans, 8. In the 13C NMR experiments, the parameters
°
were as follows: spectral window, 250 ppm; width of 30 pulse,
2.8 µs; relaxation delay, 2 s; and number of scans, 9000–10 000. 1H,
13C, COSY, HETCOR and FLOCK spectra were obtained using
standard JEOL software.
Heteronuclear 13C–1H HETCOR experiments were carried out
with a spectral width of 17 000 Hz for 13C (F2) and 4000 Hz for 1H
(F1). The spectra were acquired with 1024 ð 128 data points. The
data were processed by exponential multiplication (LB: 3Hz) in F2
and sinusoidal multiplication in F1 and zero filling was applied in
F1. The mixing delay for single-bond correlation was 3.4 ms and for
long-range bond correlation it was 70 ms and the relaxation delay
was 1.5 s.
Ł
´
Correspondence to: Jaime E. Charris, Laboratorio de Sıntesis Orga´nica,
Two-dimensional inverse hydrogen detected heteronuclear shift
correlation HMQC spectra and long-range correlation HMBC were
obtained with the standard Bruker pulse program [1J(C,H): 140 Hz,
F2 27 930 Hz and F1 5040 Hz, relaxation delay 1.5 s, 2K ð 128 data
points. 2J(C,H): 7 Hz, F2 27 930 Hz and F1 6666 Hz, relaxation delay
2.0 s, 2K ð 128 data points].
Universidad Central de Venezuela, Aptdo. 47206, Los Chaguaramos 1041-A,
Caracas, Venezuela.
Contract/grant sponsor: IIF.
Contract/grant sponsor: CDCH-UCV; Contract/grant number: PG
06-30-4590-2000.
Contract/grant sponsor: CONICIT; Contract/grant number: LAB-97000665.
Copyright 2002 John Wiley & Sons, Ltd.
Charris, Jaime E.
