# Synthesis and Bioevaluation of Novel Imatinib Base Derivatives via 1,1′-Carbonyldiimidazole Catalyst

Authors: M. J. Patoliya; G. J. Kharadi
Journal: Journal of Chemistry
 (2013)

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## Abstract

A series of eleven compounds were synthesized from 6-methyl-N′-(4-(pyridine-3-yl)pyrimidin-2-yl)benzene-1,3-diamine with various substituted carboxylic acid under solvent-free conditions using 1,1′-carbonyldiimidazole (CDI) as a catalyst. The yields of compounds are more than 72%. All the compounds were characterized by physical, spectroscopic, and elemental analysis. Compound8b exhibited good inhibition towards antimicrobial activity compared to the other compounds.


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## Body

## 1. Introduction

Imatinib mesylates (Gleevec, N-(4-methyl-3-(4-(pyridin-3-yl)-pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamidemethanesulfonate, STI571) base is known as an inhibitor of tyrosine kinases and is indicated for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs) [1–8]. Imatinib represents the first in a class of drugs targeted against chronic myelogenous leukemia to enter the clinic, showing excellent efficacy and specificity for Abl, Kit, and PDGFR kinases. Imatinib is a 2-phenylamino-pyrimidine derivative. It was developed by Novartis Pharma AG, Basel, Switzerland, and licensed for treatment of patients with chronic myeloid leukaemia. The 2-phenylaminopyrimidine (PAP) derivative, STI-571, (4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridine-3-yl-pyrimidin-2ylamino)phenyl]benzamidemesylate, imatinib mesylate, Gleevec) is a potent and relative selective Bcr-Abl tyrosine kinase inhibitor that has shown potent efficacy in CML patients in chronic phase [9, 10]. Although newly diagnosed patients with chronic phase disease achieve durable responses to STI-571 therapy, relapse and resistance are frequently observed in patients with advanced disease [11, 12]. Mutations in the kinase domain of Bcr-Abl have been found to be one of the main reasons of resistance to STI-571 [13].We aimed our research work towards developing an industrially feasible and cost-effective process for the preparation of imatinib and its analogues. An improved method for the preparation of imatinib is described in this paper (Figure1).Figure 1
General synthesis of ligands.


## 2. Experimental

### 2.1. Materials and Instrumentation

All reagents were of analytical reagent grade and were used without further purification. Solvents used were purified by standard procedures before use. substituted carboxylic acid was purchased from Aldrich. Melting points were determined in open capillaries on a Veego (model VMP-D) electronic apparatus and are uncorrected. Thin-layer chromatography was performed on microscope slides (2 cm · 97.5 cm) coated with silica gel G for monitoring of the reactions as well as to establish the identity and purity of the compounds. Ethyl acetate-cyclohexane was used as mobile phase and spots were visualized under UV irradiation. Elemental analysis (C, H, and N) was performed by Perkin-Elmer, USA, 2400-II CHN analyzer. FTIR spectra (4,000–400 cm−1) were recorded on a Shimadzu 8400-S spectrophotometer using KBr disks. Nuclear magnetic resonance spectra were recorded on a Varian 400 MHz spectrometer using DMF as a solvent and TMS as internal reference (chemical shifts in ∂ ppm).


### 2.2. General Procedure of Compound(8a–k)

A mixture of 6-methyl-N′(4-(pyridine-3-yl)pyrimidin-2-yl)benzene-1,3-diamine (35 mmol), substituted carboxylic acid (55 mmol) (Table1), 1,1′-Carbonyldiimidazole (55 mmol) in N,N-Dimethylformamide (5 mL) were taken in round bottom flask. The reaction mixture was heated up to 50–60°C and stirred for 8–10 hours on completion of reaction monitored by TLC (ethyl acetate : cyclohexane = 1 : 1); the reaction mixture was cooled to room temperature, and reaction mass was dumped into water. The solid separated was filtered and washed with water. Furthermore, the solid was suspended in Isopropylalcohol and stirred for 30 minute and filtered to get a pure product [14, 15].Table 1
Isolated yield of compounds8a–k.
Entry
R (substituent)
Isolated yield (%)
8a
82%
8b
80%
8c
76%
8d
85%
8e
72%
8f
75%
8g
80%
8h
77%
8i
79%
8j
82%
8k
81%


#### 2.2.1. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8a

Off white, Yield 82%; m.p. 170°C;1H NMR (400 MHz, DMF), 7.63(m, 2H), 8.03(d, 2H), 7.70(t, 1H), 9.15(Sec. –NH), 6.83(m, 1H), 6.92(m, 1H), 6.96(m, 1H), 4.0(Ar–NH), 2.12(s, 3H), 8.60(d, 1H), 7.24(d, 1H), 8.42(d, 1H), 9.24(s, 1H), 7.57(t, 1H), 8.70(m, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 133.0, 124.6, 134.2, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 127.5, 124.0, 134.0, 127.5, 128.8, 128.8, 132.1 CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 382 (M+1) Anal. Calc. for C23H19N5O (381.43): C, 72.42; H, 5.02; N, 18.36 Found: C, 72.36; H, 5.00; N, 18.16.


#### 2.2.2.  2-Hydroxy-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8b

Off white, Yield 80%; m.p. 178°C;1H NMR (400 MHz, DMF), 7.19(t, 1H), 7.53(t, 1H), 7.86(d, 1H), 6.95(d, 1H), 5.35(–OH), 9.15(Sec. –NH), 4.0(Ar–NH), 2.12(s, 3H), 8.60(d, 1H), 7.24(m, 1H), 8.42(d, 1H), 9.24(s, 1H), 7.57(t, 1H), 8.70(d, 1H), 6.83(m, 1H), 6.92(m, 1H), 6.96(m, 1H); 13C NMR (100 MHz, DMF), C = 159.4, 168.6, 157.9, 142.2, 133.7, 133.0, 119.8, 124.6, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 117.8, 124.0, 134.0, 128.9, 133.5, 121.4, CH3 = 17.6; FTIR (KBr): 3446 cm−1 (Aromatic O–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching),     713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 398.23 (M+1) Anal. Calc. for C23H19N5O2 (397.43): C, 69.51; H, 4.82; N, 17.62 Found: C, 69.49; H, 4.62; N, 17.59.


#### 2.2.3.  2-Hydroxy-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-2-phenylacetamide8c

Off white, Yield 76%; m.p. 180°C;1H NMR (400 MHz, DMF), 3.65(–OH), 4.0(Ar–NH), 7.23(Sec. NH), 7.36(d, 2H), 7.38(d, 2H), 7.38(d, 1H), 5.45(s, 1H), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.60(d, 1H), 7.24(d, 1H), 8.42(d, 1H), 7.57(m, 1H), 8.7(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 136.3, 133.0, 124.6, 139.1, 168.2, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130, 129.6, 124, 134, 129.6, 129.2, 129.2, 127.6, 74, CH3 = 17.6; FTIR (KBr): 3613 cm−1 (Free C–OH Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1403 cm−1 (O–H Banding), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N stretching), 1091 cm−1 (C–O Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 412 (M+1) Anal. Calc. for C24H21N5O2 (411.46): C, 70.06; H, 5.14; N, 17.02 Found: C, 70.02; H, 5.08; N, 17.00.


#### 2.2.4. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)thiophene-2-carboxamide8d

Creemish, yield 85%; m.p. 200°C;1H NMR (400 MHz, DMF), 7.27(m, 1H), 8.30(d, 1H), 8.14(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.6(d, 1H), 7.24(d, 1H), 8.42(m, 1H), 7.57(t, 1H), 8.70(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 139.4, 168.6, 157.9, 142.2, 133.7, 133, 124.6, 161.8, CH = 130.3, 131.9, 129, 157.6, 147.9, 147.6, 103.3, 107.9, 111.5, 130, 124, 134, CH3 = 17.6; FTIR (KBr): 2577 cm−1 (S–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1922 cm−1 (five member C–H Stretching), 1677 cm−1 (C=O tert. amide),    1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching),     764 cm−1 (1,2-disubstituate C-H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 386.64 (M+1) Anal. Calc. for C21H17N5OS (387.46): C, 65.10; H, 4.42; N, 18.08 Found: C, 65.02; H, 4.14; N, 18.01.


#### 2.2.5. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)pyrazine-2-carboxamide8e

Creemish, yield 72%; m.p. 220°C;1H NMR (400 MHz, DMF), 9.03(d, 1H), 8.89(d, 1H), 9.96(s, 1H), 4.0(Ar–NH), 9.15(Sec.–NH), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.6(d, 1H), 7.24(d, 1H), 8.42(m, 1H), 7.57(t, 1H), 8.70(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 137.9, 145.0, 142.2, 133.7, 133.0, 124.6, 162.6, CH = 146.0, 144.6, 157.6, 147.9, 144.7, 147.5, 103.3, 107.9, 1211.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1499 cm−1 (C=C Stretching), 1461 cm−1 (Aromatic C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 384.35 (M+2) Anal. Calc. for C21H17N7O (383.41): C, 65.79; H, 4.47; N, 25.57 Found: C, 65.69; H, 4.38; N, 25.38.


#### 2.2.6. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)pyrimidine-2-carboxamide8f

Creemish, yield 75%; m.p. 250°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 6.74(d, 1H), 7.56(d, 1H), 8.74(d, 1H), 8.82(d, 1H), 8.93(d, 1H), 8.34(d, 1H), 8.24(d, 1H), 7.19(d, 1H), 6.93(d, 1H), 6.50(d, 1H), 9.17(d, 1H), 7.2(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 158.1, 157.9, 142.2, 133.7, 133.0, 124.6, 157.9, CH = 157.6, 157.2, 147.9, 147.5, 157.2, 103.3, 123.6, 107.9, 111.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1461 cm−1 (Aromatic C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 383 (M+1) Anal. Calc. for C21H17N7O (383.41): C, 65.79; H, 4.47; N, 25.57, Found: C, 65.60; H, 4.40; N, 25.42.


#### 2.2.7.  2-Methyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8g

Off white, yield 80%; m.p. 180°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 2.20(s, 3H) 7.61(d, 1H), 7.74(d, 1H), 7.45(d, 1H), 7.72(d, 1H), 8.88(d, 1H), 7.19(d, 1H), 7.93(d, 1H), 7.14(d, 1H), 6.89(d, 1H), 6.45(d, 1H), 8.79(d, 1H), 8.97(d, 1H), 7.24(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 133.0, 136.5, 132.7, 124.6, 160.3, CH = 157.6, 147.9, 147.5, 107.9, 103.3, 111.5, 130.0, 124.0, 134.0, 127.4, 131.5, 128.7, 132, CH3 = 18.1, 17.6; FTIR (KBr): 2931 cm−1 (Alkane C–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching),     713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 396 (M+1) Anal. Calc. for C24H21N5O (395.46): C, 72.89; H, 5.35; N, 17.71 Found: C, 72.77; H, 5.26; N, 17.66.


#### 2.2.8.  4-Amino-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8h

Off white, yield 77%; m.p. 210°C;1H NMR (400 MHz, DMF), 2.19(s, 3H), 7.36(d, 1H), 7.86(d, 1H), 8.86(d, 1H), 7.92(d, 1H), 7.08(d, 1H), 7.08(d, 1H), 6.92(d, 1H), 6.63(d, 1H), 7.47(d, 1H), 7.47(d, 1H), 8.79(d, 1H), 8.97(d, 1H), 7.23(d, 1H), 9.15(Sec. –NH), 6.27 (Ar–NH2), 4.0(Ar–NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 151.8, 133.0, 124.6, 124.2, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 114.3, 130.0, 130.2, 124.0, 114.3, 134.0, 130.2, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1639 cm−1 (primary amine N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1189 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 398 (M+1) Anal. Calc. for C23H20N6O (396.44): C, 69.68; H, 5.08; N, 21.20 Found: C, 69.61; H, 5.04; N, 21.16.


#### 2.2.9. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-1h-imidazole-5-carboxamide8i

Creemish, yield 79%; m.p. 215°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.42(d, 1H), 8.84(d, 1H), 8.31(d, 1H), 8.16(d, 1H), 8.16(d, 1H), 7.19(d, 1H), 6.98(d, 1H), 6.48(d, 1H), 9.17(d, 1H), 7.68(d, 1H), 7.18(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH), 13.0(Imidazole –NH); 13C NMR (100 MHz, DMF), C = 136.7, 168.6, 157.9, 142.2, 133.7, 133.0, 124.6, 162.6, CH = 145.0, 133.6, 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 3246 cm−1 (Secondary amine N–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1554 cm−1 (Aromatic C–N Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 372.76 (M+1) Anal. Calc. for C20H17N7O (371.40): C, 64.68; H, 4.61; N, 26.40 Found: C, 64.62; H, 4.59; N, 26.26.


#### 2.2.10. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-3-nitrobenzamide8j

Off white, yield 82%; m.p. 230°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.56(d, 1H), 7.98(d, 1H), 8.71(d, 1H), 8.34(d, 1H), 8.08(d, 1H), 8.16(d, 1H), 7.88(d, 1H), 6.98(d, 1H), 7.15(d, 1H), 6.48(d, 1H), 9.17(d, 1H), 8.82(d, 1H), 7.18(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 148.0, 142.2, 133.7, 133.0, 124.6, 135.1, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 123.3, 111.5, 130.0, 133.6, 124.0, 127.3, 134.0, 129.7, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1521 cm−1 (Nitro Compound N–O stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 863 cm−1 (1,3-disubstituate C–H Stretching), 794 cm−1 (1,4-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 428 (M+1) Anal. Calc. for C23H18N6O3 (426.43): C, 64.78; H, 4.25; N, 19.71 Found: C, 64.60; H, 4.21; N, 19.48.


#### 2.2.11. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-nitrobenzamide8k

Creemish, yield 81%; m.p. 233°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.42(d, 1H), 8.63(d, 1H), 8.31(d, 1H), 8.15(d, 1H), 7.01(d, 1H), 7.15(d, 1H), 6.48(d, 1H), 8.12(d, 1H), 8.12(d, 1H), 8.14(d, 1H), 8.14(d, 1H), 7.17(d, 1H), 7.19(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 151.3, 142.2, 133.7, 133.0, 124.6, 136.8, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 124.0, 111.5, 130.0, 129.6, 124.0, 124.0, 134.0, 129.6, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 783 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 427 (M+1) Anal. Calc. for C23H18N6O3 (426.43): C, 64.78; H, 4.25; N, 19.71 Found: C, 64.70; H, 4.13; N, 19.70.


### 2.3. Antibacterial Activity

Antibacterial activity of the synthesized compounds was determined against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Xanthomonas malvacearum) in DMF by disc diffusion method on nutrient agar medium [16]. The sterile medium (nutrient agar medium, 15 mL) in each petri plates was uniformly smeared with cultures of Gram-positive and Gram-negative bacteria. Sterile discs of 10 mm diameter (Hi-Media) were made in each of the petri plates to which 50 μL (1 mg/mL, that is, 50 μg/disc) of the different synthesized compounds was added. The treatments also included 50 μL of DMF as negative control and streptomycin (1 mg/mL; 10 μg/disc) as positive control for comparison. For each treatment, three replicates were maintained. The plates were incubated at 37 ± 2°C for 24 h, and the size of the resulting zone of inhibition, if any, was determined.


### 2.4. Antifungal Activity

The synthesized compounds were screened for their antifungal activity againstFusarium oxysporum in DMF by poisoned food technique [17]. Potato dextrose agar (PDA) media were prepared, and about 15 mL of PDA was poured into each petri plate and allowed to solidify. 5 mm disc of seven-day-old culture of the test fungi was placed at the center of the petri plates and incubated at 26°C for 7 days. After incubation, the percentage inhibition was measured and three replicates were maintained for each treatment. Nystatin was used as standard. All the synthesized compounds and nystatin were tested (at the dosage of 500 μL of the compounds/petri plate, where concentration was 0.1 mg/mL) by poisoned food technique.


## 2.1. Materials and Instrumentation

All reagents were of analytical reagent grade and were used without further purification. Solvents used were purified by standard procedures before use. substituted carboxylic acid was purchased from Aldrich. Melting points were determined in open capillaries on a Veego (model VMP-D) electronic apparatus and are uncorrected. Thin-layer chromatography was performed on microscope slides (2 cm · 97.5 cm) coated with silica gel G for monitoring of the reactions as well as to establish the identity and purity of the compounds. Ethyl acetate-cyclohexane was used as mobile phase and spots were visualized under UV irradiation. Elemental analysis (C, H, and N) was performed by Perkin-Elmer, USA, 2400-II CHN analyzer. FTIR spectra (4,000–400 cm−1) were recorded on a Shimadzu 8400-S spectrophotometer using KBr disks. Nuclear magnetic resonance spectra were recorded on a Varian 400 MHz spectrometer using DMF as a solvent and TMS as internal reference (chemical shifts in ∂ ppm).


## 2.2. General Procedure of Compound(8a–k)

A mixture of 6-methyl-N′(4-(pyridine-3-yl)pyrimidin-2-yl)benzene-1,3-diamine (35 mmol), substituted carboxylic acid (55 mmol) (Table1), 1,1′-Carbonyldiimidazole (55 mmol) in N,N-Dimethylformamide (5 mL) were taken in round bottom flask. The reaction mixture was heated up to 50–60°C and stirred for 8–10 hours on completion of reaction monitored by TLC (ethyl acetate : cyclohexane = 1 : 1); the reaction mixture was cooled to room temperature, and reaction mass was dumped into water. The solid separated was filtered and washed with water. Furthermore, the solid was suspended in Isopropylalcohol and stirred for 30 minute and filtered to get a pure product [14, 15].Table 1
Isolated yield of compounds8a–k.
Entry
R (substituent)
Isolated yield (%)
8a
82%
8b
80%
8c
76%
8d
85%
8e
72%
8f
75%
8g
80%
8h
77%
8i
79%
8j
82%
8k
81%


### 2.2.1. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8a

Off white, Yield 82%; m.p. 170°C;1H NMR (400 MHz, DMF), 7.63(m, 2H), 8.03(d, 2H), 7.70(t, 1H), 9.15(Sec. –NH), 6.83(m, 1H), 6.92(m, 1H), 6.96(m, 1H), 4.0(Ar–NH), 2.12(s, 3H), 8.60(d, 1H), 7.24(d, 1H), 8.42(d, 1H), 9.24(s, 1H), 7.57(t, 1H), 8.70(m, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 133.0, 124.6, 134.2, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 127.5, 124.0, 134.0, 127.5, 128.8, 128.8, 132.1 CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 382 (M+1) Anal. Calc. for C23H19N5O (381.43): C, 72.42; H, 5.02; N, 18.36 Found: C, 72.36; H, 5.00; N, 18.16.


### 2.2.2.  2-Hydroxy-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8b

Off white, Yield 80%; m.p. 178°C;1H NMR (400 MHz, DMF), 7.19(t, 1H), 7.53(t, 1H), 7.86(d, 1H), 6.95(d, 1H), 5.35(–OH), 9.15(Sec. –NH), 4.0(Ar–NH), 2.12(s, 3H), 8.60(d, 1H), 7.24(m, 1H), 8.42(d, 1H), 9.24(s, 1H), 7.57(t, 1H), 8.70(d, 1H), 6.83(m, 1H), 6.92(m, 1H), 6.96(m, 1H); 13C NMR (100 MHz, DMF), C = 159.4, 168.6, 157.9, 142.2, 133.7, 133.0, 119.8, 124.6, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 117.8, 124.0, 134.0, 128.9, 133.5, 121.4, CH3 = 17.6; FTIR (KBr): 3446 cm−1 (Aromatic O–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching),     713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 398.23 (M+1) Anal. Calc. for C23H19N5O2 (397.43): C, 69.51; H, 4.82; N, 17.62 Found: C, 69.49; H, 4.62; N, 17.59.


### 2.2.3.  2-Hydroxy-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-2-phenylacetamide8c

Off white, Yield 76%; m.p. 180°C;1H NMR (400 MHz, DMF), 3.65(–OH), 4.0(Ar–NH), 7.23(Sec. NH), 7.36(d, 2H), 7.38(d, 2H), 7.38(d, 1H), 5.45(s, 1H), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.60(d, 1H), 7.24(d, 1H), 8.42(d, 1H), 7.57(m, 1H), 8.7(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 136.3, 133.0, 124.6, 139.1, 168.2, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130, 129.6, 124, 134, 129.6, 129.2, 129.2, 127.6, 74, CH3 = 17.6; FTIR (KBr): 3613 cm−1 (Free C–OH Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1403 cm−1 (O–H Banding), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N stretching), 1091 cm−1 (C–O Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 412 (M+1) Anal. Calc. for C24H21N5O2 (411.46): C, 70.06; H, 5.14; N, 17.02 Found: C, 70.02; H, 5.08; N, 17.00.


### 2.2.4. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)thiophene-2-carboxamide8d

Creemish, yield 85%; m.p. 200°C;1H NMR (400 MHz, DMF), 7.27(m, 1H), 8.30(d, 1H), 8.14(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.6(d, 1H), 7.24(d, 1H), 8.42(m, 1H), 7.57(t, 1H), 8.70(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 139.4, 168.6, 157.9, 142.2, 133.7, 133, 124.6, 161.8, CH = 130.3, 131.9, 129, 157.6, 147.9, 147.6, 103.3, 107.9, 111.5, 130, 124, 134, CH3 = 17.6; FTIR (KBr): 2577 cm−1 (S–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1922 cm−1 (five member C–H Stretching), 1677 cm−1 (C=O tert. amide),    1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching),     764 cm−1 (1,2-disubstituate C-H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 386.64 (M+1) Anal. Calc. for C21H17N5OS (387.46): C, 65.10; H, 4.42; N, 18.08 Found: C, 65.02; H, 4.14; N, 18.01.


### 2.2.5. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)pyrazine-2-carboxamide8e

Creemish, yield 72%; m.p. 220°C;1H NMR (400 MHz, DMF), 9.03(d, 1H), 8.89(d, 1H), 9.96(s, 1H), 4.0(Ar–NH), 9.15(Sec.–NH), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.6(d, 1H), 7.24(d, 1H), 8.42(m, 1H), 7.57(t, 1H), 8.70(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 137.9, 145.0, 142.2, 133.7, 133.0, 124.6, 162.6, CH = 146.0, 144.6, 157.6, 147.9, 144.7, 147.5, 103.3, 107.9, 1211.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1499 cm−1 (C=C Stretching), 1461 cm−1 (Aromatic C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 384.35 (M+2) Anal. Calc. for C21H17N7O (383.41): C, 65.79; H, 4.47; N, 25.57 Found: C, 65.69; H, 4.38; N, 25.38.


### 2.2.6. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)pyrimidine-2-carboxamide8f

Creemish, yield 75%; m.p. 250°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 6.74(d, 1H), 7.56(d, 1H), 8.74(d, 1H), 8.82(d, 1H), 8.93(d, 1H), 8.34(d, 1H), 8.24(d, 1H), 7.19(d, 1H), 6.93(d, 1H), 6.50(d, 1H), 9.17(d, 1H), 7.2(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 158.1, 157.9, 142.2, 133.7, 133.0, 124.6, 157.9, CH = 157.6, 157.2, 147.9, 147.5, 157.2, 103.3, 123.6, 107.9, 111.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1461 cm−1 (Aromatic C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 383 (M+1) Anal. Calc. for C21H17N7O (383.41): C, 65.79; H, 4.47; N, 25.57, Found: C, 65.60; H, 4.40; N, 25.42.


### 2.2.7.  2-Methyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8g

Off white, yield 80%; m.p. 180°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 2.20(s, 3H) 7.61(d, 1H), 7.74(d, 1H), 7.45(d, 1H), 7.72(d, 1H), 8.88(d, 1H), 7.19(d, 1H), 7.93(d, 1H), 7.14(d, 1H), 6.89(d, 1H), 6.45(d, 1H), 8.79(d, 1H), 8.97(d, 1H), 7.24(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 133.0, 136.5, 132.7, 124.6, 160.3, CH = 157.6, 147.9, 147.5, 107.9, 103.3, 111.5, 130.0, 124.0, 134.0, 127.4, 131.5, 128.7, 132, CH3 = 18.1, 17.6; FTIR (KBr): 2931 cm−1 (Alkane C–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching),     713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 396 (M+1) Anal. Calc. for C24H21N5O (395.46): C, 72.89; H, 5.35; N, 17.71 Found: C, 72.77; H, 5.26; N, 17.66.


### 2.2.8.  4-Amino-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8h

Off white, yield 77%; m.p. 210°C;1H NMR (400 MHz, DMF), 2.19(s, 3H), 7.36(d, 1H), 7.86(d, 1H), 8.86(d, 1H), 7.92(d, 1H), 7.08(d, 1H), 7.08(d, 1H), 6.92(d, 1H), 6.63(d, 1H), 7.47(d, 1H), 7.47(d, 1H), 8.79(d, 1H), 8.97(d, 1H), 7.23(d, 1H), 9.15(Sec. –NH), 6.27 (Ar–NH2), 4.0(Ar–NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 151.8, 133.0, 124.6, 124.2, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 114.3, 130.0, 130.2, 124.0, 114.3, 134.0, 130.2, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1639 cm−1 (primary amine N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1189 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 398 (M+1) Anal. Calc. for C23H20N6O (396.44): C, 69.68; H, 5.08; N, 21.20 Found: C, 69.61; H, 5.04; N, 21.16.


### 2.2.9. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-1h-imidazole-5-carboxamide8i

Creemish, yield 79%; m.p. 215°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.42(d, 1H), 8.84(d, 1H), 8.31(d, 1H), 8.16(d, 1H), 8.16(d, 1H), 7.19(d, 1H), 6.98(d, 1H), 6.48(d, 1H), 9.17(d, 1H), 7.68(d, 1H), 7.18(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH), 13.0(Imidazole –NH); 13C NMR (100 MHz, DMF), C = 136.7, 168.6, 157.9, 142.2, 133.7, 133.0, 124.6, 162.6, CH = 145.0, 133.6, 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 3246 cm−1 (Secondary amine N–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1554 cm−1 (Aromatic C–N Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 372.76 (M+1) Anal. Calc. for C20H17N7O (371.40): C, 64.68; H, 4.61; N, 26.40 Found: C, 64.62; H, 4.59; N, 26.26.


### 2.2.10. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-3-nitrobenzamide8j

Off white, yield 82%; m.p. 230°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.56(d, 1H), 7.98(d, 1H), 8.71(d, 1H), 8.34(d, 1H), 8.08(d, 1H), 8.16(d, 1H), 7.88(d, 1H), 6.98(d, 1H), 7.15(d, 1H), 6.48(d, 1H), 9.17(d, 1H), 8.82(d, 1H), 7.18(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 148.0, 142.2, 133.7, 133.0, 124.6, 135.1, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 123.3, 111.5, 130.0, 133.6, 124.0, 127.3, 134.0, 129.7, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1521 cm−1 (Nitro Compound N–O stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 863 cm−1 (1,3-disubstituate C–H Stretching), 794 cm−1 (1,4-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 428 (M+1) Anal. Calc. for C23H18N6O3 (426.43): C, 64.78; H, 4.25; N, 19.71 Found: C, 64.60; H, 4.21; N, 19.48.


### 2.2.11. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-nitrobenzamide8k

Creemish, yield 81%; m.p. 233°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.42(d, 1H), 8.63(d, 1H), 8.31(d, 1H), 8.15(d, 1H), 7.01(d, 1H), 7.15(d, 1H), 6.48(d, 1H), 8.12(d, 1H), 8.12(d, 1H), 8.14(d, 1H), 8.14(d, 1H), 7.17(d, 1H), 7.19(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 151.3, 142.2, 133.7, 133.0, 124.6, 136.8, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 124.0, 111.5, 130.0, 129.6, 124.0, 124.0, 134.0, 129.6, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 783 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 427 (M+1) Anal. Calc. for C23H18N6O3 (426.43): C, 64.78; H, 4.25; N, 19.71 Found: C, 64.70; H, 4.13; N, 19.70.


## 2.2.1. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8a

Off white, Yield 82%; m.p. 170°C;1H NMR (400 MHz, DMF), 7.63(m, 2H), 8.03(d, 2H), 7.70(t, 1H), 9.15(Sec. –NH), 6.83(m, 1H), 6.92(m, 1H), 6.96(m, 1H), 4.0(Ar–NH), 2.12(s, 3H), 8.60(d, 1H), 7.24(d, 1H), 8.42(d, 1H), 9.24(s, 1H), 7.57(t, 1H), 8.70(m, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 133.0, 124.6, 134.2, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 127.5, 124.0, 134.0, 127.5, 128.8, 128.8, 132.1 CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 382 (M+1) Anal. Calc. for C23H19N5O (381.43): C, 72.42; H, 5.02; N, 18.36 Found: C, 72.36; H, 5.00; N, 18.16.


## 2.2.2.  2-Hydroxy-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8b

Off white, Yield 80%; m.p. 178°C;1H NMR (400 MHz, DMF), 7.19(t, 1H), 7.53(t, 1H), 7.86(d, 1H), 6.95(d, 1H), 5.35(–OH), 9.15(Sec. –NH), 4.0(Ar–NH), 2.12(s, 3H), 8.60(d, 1H), 7.24(m, 1H), 8.42(d, 1H), 9.24(s, 1H), 7.57(t, 1H), 8.70(d, 1H), 6.83(m, 1H), 6.92(m, 1H), 6.96(m, 1H); 13C NMR (100 MHz, DMF), C = 159.4, 168.6, 157.9, 142.2, 133.7, 133.0, 119.8, 124.6, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 117.8, 124.0, 134.0, 128.9, 133.5, 121.4, CH3 = 17.6; FTIR (KBr): 3446 cm−1 (Aromatic O–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching),     713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 398.23 (M+1) Anal. Calc. for C23H19N5O2 (397.43): C, 69.51; H, 4.82; N, 17.62 Found: C, 69.49; H, 4.62; N, 17.59.


## 2.2.3.  2-Hydroxy-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-2-phenylacetamide8c

Off white, Yield 76%; m.p. 180°C;1H NMR (400 MHz, DMF), 3.65(–OH), 4.0(Ar–NH), 7.23(Sec. NH), 7.36(d, 2H), 7.38(d, 2H), 7.38(d, 1H), 5.45(s, 1H), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.60(d, 1H), 7.24(d, 1H), 8.42(d, 1H), 7.57(m, 1H), 8.7(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 136.3, 133.0, 124.6, 139.1, 168.2, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130, 129.6, 124, 134, 129.6, 129.2, 129.2, 127.6, 74, CH3 = 17.6; FTIR (KBr): 3613 cm−1 (Free C–OH Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1403 cm−1 (O–H Banding), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N stretching), 1091 cm−1 (C–O Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 412 (M+1) Anal. Calc. for C24H21N5O2 (411.46): C, 70.06; H, 5.14; N, 17.02 Found: C, 70.02; H, 5.08; N, 17.00.


## 2.2.4. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)thiophene-2-carboxamide8d

Creemish, yield 85%; m.p. 200°C;1H NMR (400 MHz, DMF), 7.27(m, 1H), 8.30(d, 1H), 8.14(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.6(d, 1H), 7.24(d, 1H), 8.42(m, 1H), 7.57(t, 1H), 8.70(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 139.4, 168.6, 157.9, 142.2, 133.7, 133, 124.6, 161.8, CH = 130.3, 131.9, 129, 157.6, 147.9, 147.6, 103.3, 107.9, 111.5, 130, 124, 134, CH3 = 17.6; FTIR (KBr): 2577 cm−1 (S–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1922 cm−1 (five member C–H Stretching), 1677 cm−1 (C=O tert. amide),    1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching),     764 cm−1 (1,2-disubstituate C-H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 386.64 (M+1) Anal. Calc. for C21H17N5OS (387.46): C, 65.10; H, 4.42; N, 18.08 Found: C, 65.02; H, 4.14; N, 18.01.


## 2.2.5. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)pyrazine-2-carboxamide8e

Creemish, yield 72%; m.p. 220°C;1H NMR (400 MHz, DMF), 9.03(d, 1H), 8.89(d, 1H), 9.96(s, 1H), 4.0(Ar–NH), 9.15(Sec.–NH), 6.92(d, 1H), 6.83(s, 1H), 6.96(d, 1H), 2.12(s, 3H), 8.6(d, 1H), 7.24(d, 1H), 8.42(m, 1H), 7.57(t, 1H), 8.70(d, 1H), 9.24(s, 1H); 13C NMR (100 MHz, DMF), C = 168.6, 137.9, 145.0, 142.2, 133.7, 133.0, 124.6, 162.6, CH = 146.0, 144.6, 157.6, 147.9, 144.7, 147.5, 103.3, 107.9, 1211.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1499 cm−1 (C=C Stretching), 1461 cm−1 (Aromatic C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 384.35 (M+2) Anal. Calc. for C21H17N7O (383.41): C, 65.79; H, 4.47; N, 25.57 Found: C, 65.69; H, 4.38; N, 25.38.


## 2.2.6. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)pyrimidine-2-carboxamide8f

Creemish, yield 75%; m.p. 250°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 6.74(d, 1H), 7.56(d, 1H), 8.74(d, 1H), 8.82(d, 1H), 8.93(d, 1H), 8.34(d, 1H), 8.24(d, 1H), 7.19(d, 1H), 6.93(d, 1H), 6.50(d, 1H), 9.17(d, 1H), 7.2(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 158.1, 157.9, 142.2, 133.7, 133.0, 124.6, 157.9, CH = 157.6, 157.2, 147.9, 147.5, 157.2, 103.3, 123.6, 107.9, 111.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1461 cm−1 (Aromatic C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 383 (M+1) Anal. Calc. for C21H17N7O (383.41): C, 65.79; H, 4.47; N, 25.57, Found: C, 65.60; H, 4.40; N, 25.42.


## 2.2.7.  2-Methyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8g

Off white, yield 80%; m.p. 180°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 2.20(s, 3H) 7.61(d, 1H), 7.74(d, 1H), 7.45(d, 1H), 7.72(d, 1H), 8.88(d, 1H), 7.19(d, 1H), 7.93(d, 1H), 7.14(d, 1H), 6.89(d, 1H), 6.45(d, 1H), 8.79(d, 1H), 8.97(d, 1H), 7.24(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 133.0, 136.5, 132.7, 124.6, 160.3, CH = 157.6, 147.9, 147.5, 107.9, 103.3, 111.5, 130.0, 124.0, 134.0, 127.4, 131.5, 128.7, 132, CH3 = 18.1, 17.6; FTIR (KBr): 2931 cm−1 (Alkane C–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching),     713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 396 (M+1) Anal. Calc. for C24H21N5O (395.46): C, 72.89; H, 5.35; N, 17.71 Found: C, 72.77; H, 5.26; N, 17.66.


## 2.2.8.  4-Amino-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide8h

Off white, yield 77%; m.p. 210°C;1H NMR (400 MHz, DMF), 2.19(s, 3H), 7.36(d, 1H), 7.86(d, 1H), 8.86(d, 1H), 7.92(d, 1H), 7.08(d, 1H), 7.08(d, 1H), 6.92(d, 1H), 6.63(d, 1H), 7.47(d, 1H), 7.47(d, 1H), 8.79(d, 1H), 8.97(d, 1H), 7.23(d, 1H), 9.15(Sec. –NH), 6.27 (Ar–NH2), 4.0(Ar–NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 142.2, 133.7, 151.8, 133.0, 124.6, 124.2, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 114.3, 130.0, 130.2, 124.0, 114.3, 134.0, 130.2, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1639 cm−1 (primary amine N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1189 cm−1 (C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 398 (M+1) Anal. Calc. for C23H20N6O (396.44): C, 69.68; H, 5.08; N, 21.20 Found: C, 69.61; H, 5.04; N, 21.16.


## 2.2.9. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-1h-imidazole-5-carboxamide8i

Creemish, yield 79%; m.p. 215°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.42(d, 1H), 8.84(d, 1H), 8.31(d, 1H), 8.16(d, 1H), 8.16(d, 1H), 7.19(d, 1H), 6.98(d, 1H), 6.48(d, 1H), 9.17(d, 1H), 7.68(d, 1H), 7.18(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH), 13.0(Imidazole –NH); 13C NMR (100 MHz, DMF), C = 136.7, 168.6, 157.9, 142.2, 133.7, 133.0, 124.6, 162.6, CH = 145.0, 133.6, 157.6, 147.9, 147.5, 103.3, 107.9, 111.5, 130.0, 124.0, 134.0, CH3 = 17.6; FTIR (KBr): 3246 cm−1 (Secondary amine N–H Stretching), 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1554 cm−1 (Aromatic C–N Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 790 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 372.76 (M+1) Anal. Calc. for C20H17N7O (371.40): C, 64.68; H, 4.61; N, 26.40 Found: C, 64.62; H, 4.59; N, 26.26.


## 2.2.10. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-3-nitrobenzamide8j

Off white, yield 82%; m.p. 230°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.56(d, 1H), 7.98(d, 1H), 8.71(d, 1H), 8.34(d, 1H), 8.08(d, 1H), 8.16(d, 1H), 7.88(d, 1H), 6.98(d, 1H), 7.15(d, 1H), 6.48(d, 1H), 9.17(d, 1H), 8.82(d, 1H), 7.18(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 148.0, 142.2, 133.7, 133.0, 124.6, 135.1, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 123.3, 111.5, 130.0, 133.6, 124.0, 127.3, 134.0, 129.7, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1521 cm−1 (Nitro Compound N–O stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 863 cm−1 (1,3-disubstituate C–H Stretching), 794 cm−1 (1,4-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 428 (M+1) Anal. Calc. for C23H18N6O3 (426.43): C, 64.78; H, 4.25; N, 19.71 Found: C, 64.60; H, 4.21; N, 19.48.


## 2.2.11. N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-nitrobenzamide8k

Creemish, yield 81%; m.p. 233°C;1H NMR (400 MHz, DMF), 2.13(s, 3H), 7.42(d, 1H), 8.63(d, 1H), 8.31(d, 1H), 8.15(d, 1H), 7.01(d, 1H), 7.15(d, 1H), 6.48(d, 1H), 8.12(d, 1H), 8.12(d, 1H), 8.14(d, 1H), 8.14(d, 1H), 7.17(d, 1H), 7.19(d, 1H), 4.0(Ar–NH), 9.15(Sec. –NH); 13C NMR (100 MHz, DMF), C = 168.6, 157.9, 151.3, 142.2, 133.7, 133.0, 124.6, 136.8, 164.7, CH = 157.6, 147.9, 147.5, 103.3, 107.9, 124.0, 111.5, 130.0, 129.6, 124.0, 124.0, 134.0, 129.6, CH3 = 17.6; FTIR (KBr): 2136 cm−1 (N=C–N Stretching), 1724.2 cm−1 (Aromatic C–H Stretching), 1677 cm−1 (C=O tert. amide), 1599 cm−1 (N–H Stretching), 1515 cm−1 (C=C·C=N Stretching), 1305 cm−1 (Aromatic C–N Stretching), 1176.1 cm−1 (C–N Stretching), 783 cm−1 (1,4-disubstituate C–H Stretching), 764 cm−1 (1,2-disubstituate C–H Stretching), 713 cm−1 (Aromatic C–H out of plane); ESI/MS m/z 427 (M+1) Anal. Calc. for C23H18N6O3 (426.43): C, 64.78; H, 4.25; N, 19.71 Found: C, 64.70; H, 4.13; N, 19.70.


## 2.3. Antibacterial Activity

Antibacterial activity of the synthesized compounds was determined against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Xanthomonas malvacearum) in DMF by disc diffusion method on nutrient agar medium [16]. The sterile medium (nutrient agar medium, 15 mL) in each petri plates was uniformly smeared with cultures of Gram-positive and Gram-negative bacteria. Sterile discs of 10 mm diameter (Hi-Media) were made in each of the petri plates to which 50 μL (1 mg/mL, that is, 50 μg/disc) of the different synthesized compounds was added. The treatments also included 50 μL of DMF as negative control and streptomycin (1 mg/mL; 10 μg/disc) as positive control for comparison. For each treatment, three replicates were maintained. The plates were incubated at 37 ± 2°C for 24 h, and the size of the resulting zone of inhibition, if any, was determined.


## 2.4. Antifungal Activity

The synthesized compounds were screened for their antifungal activity againstFusarium oxysporum in DMF by poisoned food technique [17]. Potato dextrose agar (PDA) media were prepared, and about 15 mL of PDA was poured into each petri plate and allowed to solidify. 5 mm disc of seven-day-old culture of the test fungi was placed at the center of the petri plates and incubated at 26°C for 7 days. After incubation, the percentage inhibition was measured and three replicates were maintained for each treatment. Nystatin was used as standard. All the synthesized compounds and nystatin were tested (at the dosage of 500 μL of the compounds/petri plate, where concentration was 0.1 mg/mL) by poisoned food technique.


## 3. Result and Discussion

The elemental analyses data showed good agreement between the experimentally determined values and the theoretically calculated values within the limits of permissible error. Yield and substitution of the synthesized compounds are listed in Table1.


### 3.1. Antibacterial Activity

The investigation of antibacterial screening data revealed that synthesized compounds showed comparable activity againstBacillus subtilis, Staphylococcus aureus, and Escherichia coli. Compound 8j exhibited good activity with the zone of inhibition in the range of 16 mm against pathogenic bacteria strain.


### 3.2. Antifungal Activity

The antifungal activity of synthesized compounds was evaluated and compared with standard drug nystatin. All the synthesized compounds showed moderate inhibitory activity and compound8j showed good antifungal activity with the 56.4% inhibition against F. oxysporum, compared to other compound. Among the synthesized compounds, inhibitory activity is in the order of 8j > 8a–i > 8k against tested fungi. The compound 2a exhibited good activity against fungal strain. Antimicrobial screening results of the tested compounds are shown in Table 2.Table 2
In vitro antibacterial and antifungal activities of synthesized compounds.
Diameter of inhibition zone (mm) % inhibition
B. subtilis
S. aureus
X. malvacearum
E. coli
F. oxysporum
8a
12
14
13
12
45.6
8b
14
11
11
12
47.2
8c
13
12
11
11
51.3
8d
11
17
11
13
52.7
8e
11
14
12
13
41.9
8f
13
15
14
14
44.6
8g
12
11
13
13
45.2
8h
11
12
13
13
43.2
8i
11
11
12
12
41.1
8j
13
15
16
14
56.1
8k
11
12
13
14
48.3
Streptomycin
18
20
18
19
—
Nystatin
—
—
—
—
85.2


## 3.1. Antibacterial Activity

The investigation of antibacterial screening data revealed that synthesized compounds showed comparable activity againstBacillus subtilis, Staphylococcus aureus, and Escherichia coli. Compound 8j exhibited good activity with the zone of inhibition in the range of 16 mm against pathogenic bacteria strain.


## 3.2. Antifungal Activity

The antifungal activity of synthesized compounds was evaluated and compared with standard drug nystatin. All the synthesized compounds showed moderate inhibitory activity and compound8j showed good antifungal activity with the 56.4% inhibition against F. oxysporum, compared to other compound. Among the synthesized compounds, inhibitory activity is in the order of 8j > 8a–i > 8k against tested fungi. The compound 2a exhibited good activity against fungal strain. Antimicrobial screening results of the tested compounds are shown in Table 2.Table 2
In vitro antibacterial and antifungal activities of synthesized compounds.
Diameter of inhibition zone (mm) % inhibition
B. subtilis
S. aureus
X. malvacearum
E. coli
F. oxysporum
8a
12
14
13
12
45.6
8b
14
11
11
12
47.2
8c
13
12
11
11
51.3
8d
11
17
11
13
52.7
8e
11
14
12
13
41.9
8f
13
15
14
14
44.6
8g
12
11
13
13
45.2
8h
11
12
13
13
43.2
8i
11
11
12
12
41.1
8j
13
15
16
14
56.1
8k
11
12
13
14
48.3
Streptomycin
18
20
18
19
—
Nystatin
—
—
—
—
85.2


## 4. Conclusion

We have demonstrated that reaction of 6-methyl-N′-(4-(pyridine-3-yl)pyrimidin-2-yl)benzene-1,3-diamine with various substituted carboxylic acid via catalyst using 1,1′-carbonyldiimidazole (CDI) resulted in new derivative of imatinib, which enables efficient synthesis in a single step with satisfactory overall yield. The products of this reaction are of potential medicinal interest. This approach has substantial advantages over previously described methods because of the ready availability of the starting materials and simple operations.



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*Source: 915381-2013-11-07.xml*