Synthesis of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents by Suzuki-Miyaura cross-coupling reactions

Figures & data

Figure 1 Structures of chimanine B, previously synthesized 4-(E)-pentenylpyrrolo[1,2-a]quinoxalines and new 4-(E)-alkenylpyrrolo[1,2-a]quinoxalines 1a–m.

Scheme 1 Synthesis of 4-(E)-alkenylpyrrolo[1,2-a]quinoxaline derivatives 1a–m. Reagents and conditions: (i) DMTHF, AcOH, Δ; (ii) CuSO₄, NaBH₄, EtOH, RT; (iii) CO(OCCl₃)₂, toluene, Δ; (iv) POCl₃, Δ; (v) Method A: CH₃(CH₂)₃CH = CH-B(O-C(CH₃)₂-)₂, KOH; Pd[P(C₆H₅)₃]₄, C₆H₆, Δ; Method B: CH₃(CH₂)_4-6CH = CH-B(OH)₂, Pd[P(C₆H₅)₃]₄, Na₂CO₃, C₆H₆, EtOH, Δ.; Method C: CH₃(CH₂)₇CH = CH-BF₃K, PdCl₂(dppf)·CH₂Cl₂, Cs₂CO₃, THF-H₂O, Δ.

Table I.  Physical properties of 4-(E)-alkenylpyrrolo[1,2-a]quinoxalines 1a–m.

Compound	log D7.4	mp (°C)	% Yield
1a	4.47	–	76
1b	4.70	–	72
1c	4.73	28	63
1d	4.90	–	66
1e	5.05	41	55
1f	5.10	51	59
1 g	5.05	–	52
1 h	4.77	72	42
1i	5.12	52	57
1j	5.05	–	71
1k	4.83	–	56
1 l	5.09	30	66
1m	4.98	49	69

Table II.  In vitro sensitivity of compounds 1a–m on L. amazonensis and L infantum strains, and cytotoxicity on human peripheral blood mononuclear cells PBMNC + PHA.

	IC50 values (μM)^a			Index of selectivity^b
	Leishmania strains		Cytotoxicity on activated human peripheral blood mononuclear cells (PBMNC)	L. amazonensis	L. infantum
Compound	L. amazonensis promastigotes	L. infantum promastigotes	PBMNC + PHA
Amphotericin B	1 ± 0.2	0.9 ± 0.1	96 ± 10	96	106.6
Chimanine B	5 ± 1	7 ± 2	42 ± 4	8.4	6
1a	0.5 ± 0.1	0.6 ± 0.1	7 ± 0.5	14	11.7
1b	2 ± 0.1	2.5 ± 0.1	5 ± 0.5	2.5	2
1c	2.5 ± 0.1	2.5 ± 0.1	5 ± 0.5	2	2
1d	1 ± 0.1	1.5 ± 0.2	7 ± 0.4	7	4.7
1e	2 ± 0.1	0.5 ± 0.1	5 ± 0.4	2.5	10
1f	2.5 ± 0.1	5 ± 0.2	10 ± 1	4	2
1 g	0.5 ± 0.1	0.6 ± 0.1	8 ± 0.5	16	13.3
1 h	2 ± 0.3	1.2 ± 0.1	8 ± 0.6	4	6.7
1i	7 ± 0.1	5 ± 0.1	20 ± 3	2.8	4
1j	3 ± 0.1	3 ± 0.1	7 ± 0.5	2.3	2.3
1k	2 ± 0.2	4 ± 0.1	5 ± 0.6	2.5	1.25
1 l	4 ± 0.4	3 ± 0.2	7 ± 0.4	1.75	2.3
1m	1 ± 0.2	4 ± 1	5 ± 0.4	5	1.25

^aIC₅₀ values were measured on the promastigotes of the Leishmania amazonensis (MHOM/BR/1987/BA) and Leishmania infantum (clone MCAN/GR/82/LEM497) strains. The IC₅₀ (μM) values correspond to the mean +/ − standard deviation from 3 independent experiments

^bIndex of selectivity (I.S.) was defined as the ratio between the IC₅₀ value on the PBMNC + PHA cells and the IC₅₀ value against the Leishmania amazonensis and Leishmania infantum strains.

Figure 2 Log D / activity relationship for pyrrolo[1,2-a]quinoxalines 1a–m L. amazonensis and L. infantum strains.