Synthesis and biological screening of some pyridine derivatives as anti-malarial agents

Figures & data

Figure 1.  Chemical structures of pyridine derivatives having anti-malarial activity.

Table 1.  Physical and analytical data of compounds 2a–h, 4a–e and 5.

Compound	Yield %	Melting point (°C)	Molecular formula (MW)
2a	81	245–250	C13H11N3O2 (241.08)
2b	84	258–259	C13H10FN3O (243.23)
2c	85	251–252	C13H10FN3O (243.23)
2d	82	260–261	C13H10FN3O (243.23)
2e	86	225–227	C13H10N4O3 (270.08)
2f	78	237–239	C15H16N4O (268.13)
2g	87	228–230	C14H13N3O3 (271.09)
2h	58	208–210	C15H13N3O (251.10)
4a	84	272–273	C18H11FN2O (290.29)
4b	89	281–282	C18H11FN2O (290.29)
4c	87	267–268	C18H11FN2O (290.29)
4d	89	280–281	C18H11N3O3 (317.08)
4e	61	271–272	C20H14N2O (298.11)
5	76	127–128	C14H16N2O2 (244.28)

Table 2.  Spectral data of compounds 2a–h, 4a–e and 5.

Compound	IR (KBr, cm^−1)	^1H NMR (DMSO-d6)
2a	3522 (OH), 3207 (NH), 1668 (C=O), 1652 (C=N)	6.91 (d, 2H, J = 8.80 Hz, phenyl–C2,6 H), 7.75 (d, 2H, J = 8.80 Hz, phenyl–C3,5H), 7.95 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.37 (s, 1H, CH=N), 8.82 (d, 2H, J = 5.78 Hz, pyridine–C-αH).
2b	3218 (NH), 1669 (C=O), 1654 (C=N)	7.21–7.62 (m, 4H, phenyl–H), 7.93 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.32 (s, 1H, CH=N), 8.81 (d, 2H, J = 5.78 Hz, pyridine–C-αH).
2c	3220 (NH), 1666 (C=O), 1655 (C=N)	7.01–7.72 (m, 4H, phenyl–H), 7.89 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.40 (s, 1H, CH=N), 8.84 (d, 2H, J = 5.78 Hz, pyridine–C-αH).
2d	3215 (NH), 1667 (C=O), 1653 (C=N)	7.18 (d, 2H, J = 8.80 Hz, phenyl–C3,5H), 7.72(d, 2H, J = 8.80 Hz, phenyl–C2,6H), 7.91 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.39 (s, 1H, CH=N), 8.81 (d, 2H, J = 5.78 Hz, pyridine–C-αH).
2e	3209 (NH), 1670 (C=O), 1656 (C=N), 1522, 1305 (NO2)	7.72–8.11 (m, 3H, phenyl–C4,5,6H), 8.22 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.39 (s, 1H, CH=N), 8.85 (d, 2H, J = 5.78 Hz, pyridine–C-αH), 8.90 (s, 1H, phenyl–C3H).
2f	3219 (NH), 1664 (C=O), 1656 (C=N)	2.16 (s, 6H, N–CH3)2), 6.52(d, 2H, J = 8.80 Hz, phenyl–C3,5H), 6.73(d, 2H, J = 8.80 Hz, phenyl–C2,6H), 7.93 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.21 (s, 1H, CH=N), 8.82 (d, 2H, J = 5.78 Hz, pyridine–C-αH).
2g	3542 (OH), 3227 (NH), 1665 (C=O), 1657 (C=N)	3.81 (s, 3H,−OCH3), 6.90 (d, 1H, J = 8.42 Hz, phenyl–C5H), 7.15 (d, 1H, J = 8.42 Hz, phenyl–C6H), 7.41(s, 1H, phenyl–C2H), 8.15 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.42 (s, 1H, CH=N), 8.91 (d, 2H, J = 5.78 Hz, pyridine–C-αH).
2h	3124 (NH), 1662 (C=O), 1651 (C=N)	6.95 (m, 2H, phenyl–CH=CH–), 7.32–7.61 (m, 5H, phenyl–H), 8.23 (d, 1H, CH=N), 8.38 (d, 2H, J = 5.78 Hz, pyridine–C-βH), 8.89 (d, 2H, J = 5.78 Hz, pyridine–C-αH).
4a	3284 (NH), 2220 (CN), 1654 (C=O)	7.09 (s, 1H, pyridine–C5H), 7.28–7.65 (m, 9H, phenyl–H), 12.87 (br s, 1H, NH, D2O exchangeable).
4b	3278 (NH), 2215 (CN), 1652 (C=O)	7.13 (s, 1H, pyridine–C5H), 7.19–7.86 (m, 9H, phenyl–H), 12.88 (br s, 1H, NH, D2O exchangeable).
4c	3274 (NH), 2217 (CN), 1649 (C=O)	6.92 (d, 2H, J = 8.80 Hz, flourophenyl–C2,6H), 7.11 (s, 1H, pyridine–C5H), 7.36–7.78 (m, flourophenyl–C3,5 H & phenyl–H), 12.91 (br s, 1H, NH, D2O exchangeable).
4d	3280 (NH), 2220 (CN), 1656 (C=O)	7.10 (s, 1H, pyridine–C5H), 7.22–7.94 (m, 8H, nitrophenyl–C4,5,6H & phenyl–H), 8.65 (d, 1H, J = 8.64 Hz, nitrophenyl–C3 H), 12.88 (br s, 1H, NH, D2O exchangeable).
4e	3279 (NH), 2219 (CN), 1655 (C=O)	6.67 (d, 1H, J = 5.22 Hz, Phenyl–CH=CH–),7.12 (s, 1H, pyridine–C5 H), 1.18 (d, 1H, J = 5.22 Hz, Phenyl–CH=CH–), 7.20–8.02 (m, 10H, phenyl–H), 12.89 (br s, 1H, NH, D2O exchangeable).
5	2214 (CN); 1704 (C=O); 1256, 1123 (C–O–C)	1.24 (t, 3H, CH3), 3.15 (s, 6H,−N(CH3)2), 4.35 (m, 2H, CH2), 6.71 (d, 2H, J = 8.75 Hz, phenyl C2,6H), 7.92 (d, 2H, J = 8.75 Hz, phenyl C3,5H), 8.12 (s, 1H,−C=CH).

Scheme 1.  Synthesis of hydrazone derivatives.

Scheme 2.  Synthesis of pyridone derivatives.

Table 3.  In vivo anti-malarial activity of compounds 2a–h and 4a–e.

Compound	% Parasitaemia	% Suppression	Mean survival time (days)
2a	8 ± 0.8	90	11.5 ± 0.6
2b	34 ± 1.2	58	8.2 ± 1.6
2c	32 ± 1.6	61	8.6 ± 1.9
2d	22 ± 0.4	74	9.1 ± 1.2
2e	81 ± 2.4	1	2.4 ± 0.8
2f	31 ± 1.0	63	9.22 ± 1.4
2g	15 ± 0.6	91	9.8 ± 0.5
2h	17 ± 1.3	80	9.4 ± 1.0
4a	46 ± 3.4	44	7.4 ± 1.1
4b	52 ± 2.8	37	6.8 ± 1.8
4c	31 ± 3.8	63	8.8 ± 1.4
4d	64 ± 1.8	22	4.2 ± 2.4
4e	47 ± 2.8	43	7.1 ± 1.5
Control	82 ± 1.6	0.0	6.3 ± 0.5
Chloroquine	0.0	100	ND

Table 4.  In vitro anti-plasmodial activity against chloroquine-resistant (RKL9) strain of Plasmodium falciparum.

Compound	IC50, µM ± SD*
2a	0.0422 ± 0.004
2g	0.0402 ± 0.005
2h	0.0660 ± 0.012
Chloroquine	0.188 ± 0.003

*Results of two separate determinations.

Figure 2.  3D view from a molecular modelling study, of the minimum-energy structure of the complex of WR99210 docked in DHFRE (PDB ID: 1J3I). Viewed using Molecular Operating Environment (MOE) module.

Table 5.  Calculated docking hydrogen bonding results for compounds WR99210, 2a, 2g and 2h.

Compound	Residue	Type	Score (%)	Distance
WR99210	Ile 14	H-don	28.2	1.98
	Asp 54	H-don	57.1	1.87
	Ile 164	H-don	17.8	2.20
2a	Phe 116	H-don	72.3	2.17
2g	Phe 116	H-don	13.6	2.02
	Ser 120	H-acc	90.2	2.44
2h	Ser 111	H-don	76.7	1.67

Figure 3.  3D view from a molecular modelling study, of the minimum-energy structure of the complex of 2a docked in DHFRE (PDB ID: 1J3I). Viewed using Molecular Operating Environment (MOE) module.

Figure 4.  3D view from a molecular modelling study, of the minimum-energy structure of the complex of 2g docked in DHFRE (PDB ID: 1J3I). Viewed using Molecular Operating Environment (MOE) module.

Figure 5.  3D view from a molecular modelling study, of the minimum-energy structure of the complex of 2h docked in DHFRE (PDB ID: 1J3I). Viewed using Molecular Operating Environment (MOE) module.