Bis dihydropyrimidine: synthesis and antimycobacterial activity
151
N5-(4-4-[6-(3,4,5-trimethoxy phenyl)-2-imino-4-methyl-
1,2,3,4-tetrahydro-5-pyrimidinyl carboxamido] phenyl
sulphonylphenyl)-6-(3,4,5-Trimethoxy phenyl)-2-imino-4-
methyl-1,2,3,4-tetrahydro-5-pyrimidine carboxamide (3f)
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH), 1642
carboxamide (3k)
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH), 1642
(C=O), 1320 (C-N), 786(C-F). 1H NMR (DMSO-d6)
ppm:1.37(6H, s, CH3), 2.37 (2H, s, CO=NH), 5.16–5.2 (2H,
m, CH-CH3), 6.52–7.12 (6H, m, furan), 7.52–7.98 (8H, m,
aromatic), 10.12 (6H, s, NH). Mass (m/z): 654 (M+); Cal/
Ana: [C (58.71) 58.7,H (4.58) 4.56, N(17.12) 17.10]
1
(C=O), 1320 (C-N). H NMR (DMSO-d6) ppm: 1.29–1.37
(6H, d, CH3), 2.37 (2H, s, CO=NH), 3.8 (18H, s, OCH3),
5.16–5.20 (2H, m, CH-CH3), 7.52–7.98 (12H, m, aromatic),
10.12 (6H, s, NH). Mass (m/z):854 (M+); Cal/Ana: [C
(59.01) 59.02, H (5.38) 5.37, N (13.11) 13.1]
N5-(4-4-[2-imino-4-methyl-6-(2-thienyl)-1,2,3,4-tetrahydro-
5-pyrimidinylcarbox-amido] phenylsulphonylphenyl)-2-
imino-4-methyl-6-(2-thienyl)-1,2,3,4-tetrahydro-5-pyrimidine
carboxamide (3l)
N5-(4-4-[6-(4-fluorohenyl)-2-imino-4-methyl-1,2,3,4-
tetrahydro-5-pyrimidinylcarbox- amido] phenyl
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH),
1
sulphonylphenyl)-6-(4-fluoroophenyl)-2-imino-4-
methyl-1,2,3,4-tetrahydro-5-pyrimidine carboxamide (3g)
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH), 1642
1642 (C=O), 1320 (C-N), 786(C-F). H NMR (DMSO-d6)
ppm:1.37 (6H, s, CH3), 2.37 (2H, s, CO=NH), 5.16–5.2 (2H,
m, CH-CH3), 6.08–6.92 (6H, m, thiophene),7.52–7.98 (8H,
m, aromatic), 10.12 (6H, s, NH). Mass (m/z): 686 (M+);Cal/
Ana: [C (55.97) 55.95, H (4.37) 4.36, N (18.32) 18.3]
1
(C=O), 1320 (C-N), 786(C-F). H NMR (DMSO-d6) ppm:
1.29–1.31(6H, d, CH3), 2.37 (2H, s, CO=NH), 5.16–5.2 (2H,
m, CH-CH3), 7.52–7.98 (16H, m, aromatic), 10.12 (6H, s,
NH). Mass (m/z): 710 (M+); Cal/Ana: [C (60.84) 60.81, H
(4.5) 4.49, N (15.77) 15.76]
N5-(4-4-[6-(3-hydroxy,4-methoxy)-2-imino-4-methyl-
1,2,3,4-tetrahydro-5-pyrimi- dinylcarboxamido] phenyl
sulphonylphenyl)-6-(3-Hydroxy,4-methoxy)-2-imino-4-
methyl-1,2,3,4-tetrahydro-5-pyrimidine carboxamide (3m)
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH), 1642
(C=O), 1320 (C-N), 786 (C-F). 1H NMR (DMSO-d6)
ppm:1.37 (6H, s, CH3), 2.37 (2H, s, CO=NH), 3.8 (6H, s,
OCH3), 8.42 (2H, s, OH), 5.16–5.2 (2H, m, CH-CH3), 7–7.88
(14H, m, aromatic), 8.42 (6H, s, NH). Mass (m/z): 766 (M+);
Cal/Ana: [C (59.53) 59.52, H (4.96) 4.95, N (14.62) 14.63]
N5-(4-4-[6-(2-chlorophenyl)-2-imino-4-methyl-1,2,3,4-
tetrahydro-5-pyrimidinylcarbox- amido] phenyl
sulphonylphenyl)-6-(2-Chloro phenyl)-2-imino-4-
methyl-1,2,3,4-tetrahydro-5-pyrimidine carboxamide (3h)
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH), 1642
(C=O), 1320 (C-N), 766 (C-Cl). 1H NMR (DMSO-d6) ppm:
1.29–1.31(6H, d, CH3), 2.37 (2H, s, CO=NH), 5.18–5.22
(2H, m, CH-CH3),7.62–7.78 (16H, m, aromatic),10.16 (6H,
s, NH). Mass (m/z): 743 (M+); Cal/Ana: [C (58.14) 58.13, H
(4.3) 4.31, N (15.73) 15.72]
Biology
e primary screen was conducted at 6.25μg/ml
(or at the molar equivalent of the highest molecular
weight compound in a series of congeners) against
Mycobacterium tuberculosis H37RV (ATCC27294) in
BACTEC 12B medium using the BACTEC 460 radiomet-
ric system (Alwar, Rajasthan, India)[8].
N5-(4-4-[6-(2,6-dichlorophenyl)-2-imino-4-methyl-
1,2,3,4-tetrahydro-5-pyrimidinyl carboxamido] phenyl
sulphonylphenyl)-6-(2,6-Dichloro phenyl)-2-imino-4-methyl-
1,2,3,4-tetrahydro-5-pyrimidine carboxamide (3i)
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH), 1642
(C=O), 1320 (C-N), 766 (C-Cl). 1H NMR (DMSO-d6)
ppm:1.29–1.32 (6H, d, CH3), 2.37 (2H, s, CO=NH), 5.18–
5.22 (2H, m, CH-CH3), 7.62–7.78 (14H, m, aromatic),
10.16 (6H, s, NH). Mass (m/z): 813 (M+); Cal/Ana: [C
(53.20) 53.21, H (3.69) 3.68, N(13.79) 13.78]
Cytotoxicity
All the compounds were tested for cytotoxicity using the
half maximal inhibitory concentration (1C50) in VERO
cells at concentrations at 62.5μg/mL or 10 times. After a
72 h exposure, viability was assessed on the basis of cellu-
lar conversion of 3-(4,5-dimethythiazol-2-yl)-2,5-diphe-
nyltetrazolium bromide (MTT) dye into the formazan
product using the Promega CellTiter 96® Non-radioactive
Cell proliferation method [9].
N5-(4-4-[6-(4-nitrophenyl)-2-imino-4-methyl-1,2,3,4-
tetrahydro-5-pyrimidinylcarbox-amido] phenyl
sulphonylphenyl)-6-(4-Nitro phenyl)-2-imino-4-methyl-
1,2,3,4-tetrahydro-5-pyrimidine carboxamide (3j)
IR: (KBr) cm−1: 3307 (NH), 3218 (OH), 3042 (CH), 1642
Results and discussion
1
(C=O), 1320 (C-N). H NMR (DMSO-d6) ppm: 1.3–1.34
(6H, d, CH3), 2.47 (2H, s, CO=NH), 5.26–5.3 (2H, m,
CH-CH3), 7.82–8.18 (16H, m, aromatic), 10.12 (6H, s,
NH). Mass (m/z): 764 (M+); Cal/Ana: [C (56.54) 5 56.52,
H (4.18) 4.17, N(18.32) 18.3]
Chemistry
e
tetrahydro-5-pyrimidinylcarboxamido)
sulphonyl] phenyl-2-imino-4-methyl-6-phenyl-1,2,3,4-
tetrahydro-5-pyrimidinecarboxamide compounds 3a–k
described in this study are shown in Table 1. A reaction
sequence for the preparation of the compounds is out-
lined in Scheme 1. e reaction between dapsone and
N5-4-[4-(2-imino-4-methyl-6-phenyl-1,2,3,4-
phenyl
N5-(4-4-[6-(2-furyl)-2-imino-4-methyl-1,2,3,4-tetrahydro-
5-pyrimidinylcarbox-amido] phenylsulphonylphenyl)-6-(2-
furyl)-2-imino-4-methyl-1,2,3,4-tetrahydro-5-pyrimidine
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