Sulfonamide–metal complexes endowed with potent anti-Trypanosoma cruzi activity

Figures & data

Table 1. Antiprotozoal activity, toxicity and enzyme inhibition for the sulfonamides and their metal complexes.

Compounds	Metal	Y strain T. cruzi (IC50 µM) trypomastigotes* epimastigotes†		Splenocytes (µM)‡	Trypanothione reductase inhibition (%)§
L1	–	20.4	32.9	10	NT
L2	–	39.2	20.7	25	NT
L3	–	65.8	>100	10	0
C1	Co	5.6	7.0	10	10 ± 2
C2	Ni	29.8	10.1	10	5
C3	Cu	10.5	1.1	<1.0	NT
C4	Zn	ND	ND	<1.0	NT
C5	Co	2.7	1.9	<1.0	5
C6	Ni	>100	>100	<1.0	0 ± 1
C7	Cu	5.9	10.8	<1.0	8 ± 0.5
C8	Zn	>100	>100	<1.0	NT
C9	Co	10.5	14.3	<1.0	NT
C10	Ni	45.8	59.8	<1.0	0 ± 1.5
C11	Cu	4.8	3.1	<1.0	0 ± 3
C12	Zn	ND	ND	<1.0	5 ± 3
Nfx	–	2.75	1.8	1.0	–
GV	–	–	–	0.01	–

Nfx, Nifurtimox; GV, gentian violet; ND, not determined, due to the lack of activity in the tested concentrations.

*After 24 h of incubation of cell cultures in the presence of the inhibitor. Values were calculated from seven concentrations using data obtained from at least two independent experiments (SD ± 10%).

†After 11 days of incubation of cell cultures in the presence of the inhibitor. Calculated from seven concentrations using data obtained from at least two independent experiments (SD ± 10%).

‡LC₅₀ values were calculated for BALB/c splenocytes after 24 h of incubation of the inhibitor.

§Compounds were added at 50 µM.

Figure 1. Preparation of ligands (L1–3).

Figure 2. Proposed structure of the metal(II) complexes, C1--12.

Figure 3. Top: Calculated molecular structure of complexes C1--4. Central “M” spheres represent metal (Co, Ni, Cu or Zn). W1 and W2 describe oxygen atoms belonging to water molecules. Bottom: Calculated molecular structure of complexes C5--8.

Figure 4. Calculated molecular structure of complexes C9–12.

Table 2. Calculated geometric and electronic parameters for complexes C1–12.

Complex	M–O1*	M–O2	M–N1	M–N2	M–W1	M–W2	q (M) NBO	q (M) APT	Spin (M)
1	1.981	1.999	2.217	2.212	2.240	2.272	1.40	1.44	2.68
2	2.001	2.013	2.145	2.142	2.177	2.199	1.41	1.31	1.67
3	1.950	1.953	2.082	2.073	2.553	2.660	1.31	1.23	0.58
4	2.022	2.037	2.260	2.244	2.244	2.285	1.68	1.51
5	1.986	1.986	2.186	2.184	2.274	2.272	1.40	1.42	2.67
6	1.999	2.011	2.145	2.143	2.177	2.196	1.38	1.32	1.65
7	1.952	1.952	2.071	2.071	2.601	2.576	1.31	1.25	0.58
8	2.022	2.033	2.263	2.243	2.240	2.285	1.69	1.52
9	2.010	2.004	2.155	2.163	2.303	2.274	1.41	1.47	2.68
10	2.029	2.022	2.106	2.108	2.223	2.199	1.38	1.33	1.65
11	1.957	1.971	2.058	2.047	3.045	2.484	1.29	1.23	0.57
12	2.058	2.044	2.194	2.177	2.319	2.288	1.68	1.56

*Bond lengths are given in Angstrom (M = Co for 1, 5 and 9; Ni for 2, 6 and 10; Cu for 3, 7 and 11, and Zn for 4, 8 and 12). W1 and W2 are related to water molecules.

Table 3. Calculated bond angles (°) and intramolecular hydrogen bonds (Å) for complexes C1–12.

Complex	O1–M–N1	O2–M–N2	O1–M–N2	O2–M–N1	W1–M–W2	O1–M–O2	N1–M–N2	W1H–O2	W2H–O1
1	86.2	84.5	90.5	98.8	180.0	174.8	176.6	2.033	2.078
2	84.4	86.5	90.2	95.9	179.0	176.6	178.6	1.982	2.014
3	90.2	88.1	85.5	92.2	177.5	177.4	178.9	1.962	1.990
4	85.5	83.3	90.1	101.1	177.7	173.3	173.6	1.981	2.021
5	86.2	86.2	97.7	93.9	179.6	179.8	179.9	2.048	2.035
6	88.4	86.5	90.1	95.0	179.2	176.7	178.5	2.003	2.030
7	88.8	89.0	99.9	91.2	179.5	180.0	179.2	1.987	1.978
8	85.6	83.2	89.9	101.4	177.6	172.9	173.2	1.995	2.041
9	87.1	87.6	93.9	91.5	178.7	177.3	171.6	2.022	1.935
10	88.6	88.7	91.5	91.2	178.2	178.5	177.8	1.986	1.912
11	90.6	89.6	88.6	90.8	169.4	173.6	176.6	2.035	1.933
12	86.6	87.0	93.7	92.8	177.1	177.6	178.5	1.980	1.908