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

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. Compound 8b exhibited good inhibition towards antimicrobial activity compared to the other compounds.

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 (Figure 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).

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 L (1 mg/mL, that is, 50 g/disc) of the different synthesized compounds was added.The treatments also included 50 L of DMF as negative control and streptomycin (1 mg/mL; 10 g/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 against Fusarium 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 L of the compounds/petri plate, where concentration was 0.1 mg/mL) by poisoned food technique.

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 Table 1.

Antibacterial Activity.
The investigation of antibacterial screening data revealed that synthesized compounds showed comparable activity against Bacillus 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.

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 compound 8j 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.

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.

Table 2 :
In vitro antibacterial and antifungal activities of synthesized compounds.