Synthesis and Evaluation of Antibacterial and Antifungal Activities of 1 , 3-Disubstituted-4-thioxoimidazolidin-2one Derivatives

1,3-Disubstituted-4-thioxoimidazolidin-2-one derivatives with various substituents at N1 and N3 were synthesized with high yields and excellent purity by the reaction of various N-arylcyanothioformamide derivatives with isocyanate derivatives. The activity of these products as antibacterial and antifungal agents was studied to through some light on structural activity relationship. Some of synthesized compounds showed significant antibacterial and antifungal activities. Most of the imidazole derivatives possess significant antifungal activity aginst S. cerevisiae (MIC 1–10 μg mL–1). As comparision with ketoconazole, most of the imidazole derivatives showed activity ranging from 50 % less activity to fourfold activity.


INTRODUCTION
MIDAZOLE derivatives are keys compounds in many bioactive compounds of natural and synthetic origins.Nitroimidazoles are a well-known family of antibacterial and antiprozoal drugs, including anti-trypanosomal drugs or compounds with known anti-trypanosomal activity. [1]or more than 50 years, metronidazole was the first drug introduced as antiparasit agent and it was the best-known drug in this class. [2]5][6][7] Bacterial infection and fungal infection are among the widespread and serious diseases.To overcome these serious diseases, the discovery of new types of antimicrobial agents is a very important task.0] In light of these facts, the present study was designed to synthesize new imidazole derivatives and evaluate their antimicrobial activity.As a trial to obtain novel class of antibacterial and antifungal agents, various groups were introduced into the target compounds.

EXPERIMENTAL
IR spectra were recorded (KBr) on a Perkin Elmer 1650 spectrophotometer. 1 H NMR and 13 C NMR spectra were recorded on Avance II Bruker FT NMR spectrometer 400 (400 MHz) using CDCl3 as solvents and TMS as an internal standard.CFCl3 was used as an internal standard for all 19

Antimicrobial Screening
MICs were assessed by serial broth dilution method. [12]The freshly prepard inocula were incubated for 24 h at 37 °C in NB for bacteria and 48 h at 30 °C in Sabouraud dextrose broth for fungi.The chemical compounds were first dissolved in DMSO and then different concentrations of them were prepared by diluting the samples in NB and Sabouraud dextrose broth for bacteria and fungi, respectively to reach the final concentration of 1 to 100 µg mL -1 .Each one mL from the above concentrations received 0.1 mL of the inoculum to reach 10 6 CFU mL -1 for bacteria and fungi.Triplicate tests were performed and the average was taken as the final reading comparing to negative and positive controls.

Chemistry
Cyanothioformamide derivative 1 was prepared by reaction 3,5-dichlorophenylisothiocyanate with potassium cyanide according to literature procedure. [5]The tautomeric nature of the N-arylcyanothioformamide reflects their nucleophilic character in which they may react via the nitrogen or sulfur atom leading to different ring closing reactions.Reaction of N-arylcyanothioformamide derivative 1 with various isocyanate derivatives in ether, followed by addition of a few drops of triethylamine as catalyst afforded imidazolidineiminothione derivatives 2a-h (Scheme 1).Their IR, NMR ( 1 H and 13 C) and mass spectra indicated that 5-imino-4-thioxo-2-imidazolidinone derivatives 2a-h were furnished as the sole products, indicating that the ring closing reaction proceeds via a single path which involves attack via the nitrogen atom.
It has been reported that moving side chain around the the main scaffold to the other position can result in retention of biological activities and providing new opportunities for the design of bioactive compounds. [11]These observations gave us an additional motivation to combination of the 3,5-dichlorophenyl moiety with imidazole scaffold at N-(1) of the imidazole.Therefore, treating an ethereal solution of N-arylcyanothioformamides 3a,b with 3,5-dichlorophenylisocyanate, followed by addition of a few drops of triethylamine afforded imidazolidineiminothione derivatives 4a,b.
Moreover, our investigation was extended to include the behavior of benzylisothiocyanate toward different Narylcyanothioformamides.Thus, when N-arylcyanothiofor-DOI: 10.5562/cca3354 Croat.Chem.Acta 2018, 91 (3)   mamides 5a-c were let to react with benzylisothiocyanate in ether in precence of a few drops of triethylamine, imidazolidineiminothione derivatives 6a-c were afford in good yeilds.The structure of compounds 6a-c was inferred from their correct elemental analyses and spectral data.To obtain another type of imidazole, hydrolysis of 6a-c with dilute HCl was carredout in boiling ethanol and the corresponding dione derivatives 7a-c were abtianed (Scheme 3).

Biological Activity
The aim of the present investigation is to synthesize series of imidazolidineiminothiones was bearing various substituent at N-( 1) and others at N- (3).The antibacterial and antifungal activities of these derivatives were measured.The effect of each substituent at N-( 1) and at N-(3) on these activities was studied and make a comparative study between them to deduce a structure activity relationship was made.A series of imidazolidineiminothione 2a-h containing 3,5-dichlorophenyl moiety at N-( 1

Antibacterial and Antifungal Activities
and the MIC results (µg mL -1 ) were presented in Table 1.Generaly, the mean values of the obtained MIC suggest that most of the imidazole derivatives evaluated possess significant antibacterial activity against G +ve bacteria and no results against G -ve bactria.Also, most of the imidazole derivatives evaluated possess significant antifungal.A moderate difference in the antimicrobial activity is noted between the tested compounds.This suggested that, the main effect may be related to the presence of the imidazolidinethione moiety.All of the imidazole derivatives possess significant antifungal aginst S. cerevisiae MIC (1-10 µg mL -1 ).As comparision with ketoconazole, the imidazole derivatives showed activity ranged from 50 % less activity to fourfold activity.

CONCLUSION
The synthesis, characterization and evaluation of antibacterial and antifungal activities of new series of 1,3- disubstituted-4-thioxoimidazolidin-2-one derivatives with variable substituents at N-(1) and N-(3) have been described.Some compounds displayed antibacterial and antifungal activities.Generaly, the mean values of the obtained MIC suggest that some of the imidazole derivatives evaluated possess significant antibacterial activity against G +ve bacteria and no activity against G -ve bacteria.Also, some of the imidazole derivatives possess significant antifungal effect.A moderate difference in the antimicrobial activity is noted between the tested compounds.This suggested that, the main effect may be related to the presence of the imidazolidinethione moiety.

Table 1 .
Minimum inhibitory concentration (µg mL -1 ) of the synthesized compounds against the pathological organisms.