A Convenient and Practical Synthesis of Novel Pyrimidine Derivatives and its Therapeutic Potential
Authors: Arora Kaushal , Kumar Amit , Verma Prabhakar Kumar 
Published: February 2024

Background:

A new series of 2-(2-(substituted aldehyde)hydrazinyl)-4-(2-
chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile analogs (1–19) was prepared
by using the Biginelli reaction.

Methods:

TLC was employed to ensure the progress and confirmation of the reactions. Silica gel
G was employed as the stationary phase, and mobile phases such as chloroform: toluene and acetone:
n-hexane were used for the synthesized compounds. NMR has characterized the synthesized
compound. MS IR, CHN.

Results:

The prepared derivatives were evaluated in vitro for antimicrobial activity against various
bacteria and fungi using the tube dilution technique. Notably, compounds 2-(2-(3-Ethoxy-4-
hydroxybenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-
carbonitrile T1, 2-(2-(2-Hydroxybenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-
dihydropyrimidine-5 carbonitrile T6, and 2-(2-(4-Hydroxybenzylidene)hydrazinyl)-4-(2-
chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile T16, displayed significant
antibacterial activity, surpassing the standard drug Ampicillin. In the antifungal category, compounds
2-(2-(3-Ethoxy-4-hydroxybenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyri
midine-5-carbonitrile T1, 2-(2-(3,4-Dimethoxybenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-
oxo-1,6-dihydropyrimidine-5-carbonitrile T2, and 2-(2-(2,4-Dichlorobenzylidene)hydrazinyl)-4-(2-
chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile T13, were very much effective
against both fungal strains A. niger as well as C. albicans. Furthermore, compounds 2-(2-(2-
Hydroxybenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5 carbonitrile
T6, 2-(2-(2-Nitrobenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyri
midine-5-carbonitrile T8, 2-(2-(4-Chlorobenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-
1,6-dihydropyrimidine-5-carbonitrile T12, and 2-(2-(4-Dimethylaminobenzylidene)hydrazinyl)-4-(2-
chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile T14 demonstrated remarkable
antioxidant properties, because of their low IC50 values in the DPPH assay. In the realm of anticancer
activity, 2-(2-(substituted aldehyde)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydro
pyrimidine-5-carbonitrile T9 outperformed the standard drug Adriamycin in terms of its effectiveness
against human lung cancer cells (A-549) with a GI50 value of less than 10 according to the SRB assay.
In addition, the antidiabetic assessment highlighted the excellent performance of compounds 2-(2-
(2-Nitrobenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-
carbonitrile T8, 2-(2-(4-Chlorobenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-
dihydropyrimidine-5-carbonitrile T12, and 2-(2-(3-Nitrobenzylidene)hydrazinyl)-4-(2-chloro
phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile T15, with low IC50 values, when
tested for their inhibition of α-amylase enzyme activity.

Conclusions:

The synthesized derivatives demonstrated strong antimicrobial, antioxidant, anticancer,
and antidiabetic properties when assessed using specific methods and compared to established
drugs. Notably, compounds 2-(2-(3-Ethoxy-4-hydroxybenzylidene)hydrazinyl)-4-(2-chloro
phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile T1, 2-(2-(2-Hydroxybenzylidene)
hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5 carbonitrile T6, and 2-
(2-(2,4-Dichlorobenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine
-5-carbonitrile T13, 2-(2-(4-Chlorobenzylidene)hydrazinyl)-4-(2-chlorophenyl)-1-methyl-6-oxo-
1,6-dihydropyrimidine-5-carbonitrile T12 and 2-(2-(substituted aldehyde)hydrazinyl)-4-(2-chloro
phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile T9 exhibited even higher activity levels
than the standard medications. The presence of electron-releasing groups in the synthesized
compounds enhanced their antibacterial and antioxidant effects, particularly against B. subtilis. On
the other hand, electron-withdrawing groups improved their anticancer and antidiabetic properties.