INTRODUCTION:

Imidazolidines are a class of saturated heterocyclic compounds, characterized by a five-membered ring containing two nitrogen atoms¹. Imidazolidine is an organic compound with azo group and it is more beneficial in organic synthesis. The physical properties of imidazolidine with molecular formula C₃H₈N₂, molar mass 72.11g/mol², Density-0.9±0.1g/cm³.

Boiling point: 86 to 92.8°C. Flashpoint- 9.9±10.2°C. Among the imidazolidine and imidazolidine, 2,4 dione is the most widely used scaffold and is also known as hydantoin³. The substitutions at the 2nd position improve binding affinity or pharmacokinetics in drug design and at the 4th and 5th positions enhance the selectivity and activity by optimizing molecular interactions such as hydrogen bonding and hydrophilic interactions. It has been reported that Imidazolidine derivatives possess anticancer, anti-proliferative, anti-psychotropic, anti-convulsant, anti-arrhythmic, anti-microbial, and anti-plasmodial activity allowing identifying the promising drug-like compound as per the objective of pharmaceutical chemistry. In the pharmaceutical industry, imidazolidine derivatives are used as precursors for the synthesis of therapeutic agents such as anticonvulsants, sedatives, and muscle relaxants^1-3. Moreover, their structural resemblance to biologically active natural products has inspired the development of analogs with enhanced efficacy and reduced toxicity. Imidazolidine derivatives can be synthesized through various methods, such as cyclization reactions of diamines with aldehydes or ketones and modifications of imidazole or other heterocycles. Given the imidazolidine nucleus's multitargeted functioning, our goal is to correlate the available data on multitargeted inhibitors with the nucleus. This might act as a guideline for modifying current ligands to produce novel ones with more potent binding interactions. Since aromatic-substituted imidazolidine cores are frequently found in physiologically active medications, there is a need for advanced and efficient techniques to produce the heterocyclic lead imidazolidine as a critical class of compounds for novel drug research. This review attempts to gather the statistical report of the last five years' research on the synthesis and biological activity of heterocyclic systems with imidazolidine fragments in molecules to provide researchers with a comprehensive picture of recent developments in this field.

Biological activities of Imidazolidine derivatives:

Anticancer activity: The anticancer potential of several 3-substituted-4-oxo-imidazolidin-2-(1H)-Thione derivatives (3–9) was evaluated in HepG-2 and HCT-116. Using techniques from elemental analysis and spectroscopy, including 1H, 13C NMR, MS, and IR, the chemical composition of the generated chemicals was confirmed. According to cytotoxicity screening, compounds (Z)-5-(5-bromo-2-hydroxy benzylidene)-3-((E)-(1-(4-chlorophenyl)ethylidene)amino)2thioxo imidazoline-4-one (7) and Methyl 3-((E)-5-(5-bromo-2-hydroxybenzylidene)-3-((E)-(1-(4-chlorophenyl)ethylidene)amino)-4-oxo-2-thioxoimidazolidine-1-yl) propanoate (9) demonstrated strong anti-proliferation activity against the cancer cell lines HepG-2 and HCT (Figure 1). The results of the cell cycle analysis demonstrated that compound 9, which is the most active, causes colon cancer cells to undergo apoptosis, arrests them at the S phase, and has a strong inhibitory effect on Nrf2. Compound 7 has a strong inhibitory effect on Nrf2, causes apoptosis in liver cancer, and stops liver cancer cells at the G0/G1 phase. These results suggest that the recently identified 2-thioxoimidazolin-4-one family provides a useful framework for the discovery of additional possible anticancer medications⁴.

Figure No. 1: Chemical structure of compounds 7 and 9

The anticancer potential of six new imidazolidindionedioximeplatinum (II) complexes was evaluated by Emrah Karahan et al. The low IC₅₀ value of the Pt-derived compounds suggests that they have cytotoxic effects on MDA-MB-231 and MCF-7 cancer cells. Additionally, at low concentrations, synthesized platinum complexes showed strong anticancer activity against MCF-7 cells, which leads to cell death. When compared to the conventional anticancer medications cisPt and bicalutamide, Pt-derived compounds proved to be more effective and selective. For cell cycle analysis, we thus screened every mono and bisplatinum complex. According to our findings, compounds L1aPt-m, L1aPt-b, and L1cPt-b enhance the G1 population and control the cell cycle. Additionally, the compounds effectively induced cellular apoptosis in MDA-MB-231 and MCF-7 cancer cells, according to an apoptosis assay. Bis[N-(1,3-dihydroxy-2-imidazolidinylidene)-N'-phenylmethanediimine) platinum(II) (L1aPt-b) is slightly more potent than L1cPt-b in both MCF-7 and MDA-MB-231 breast cancer cell lines, as it has slightly lower IC₅₀ values(Figure 2)⁵.

Figure No. 2: Chemical structure of Bis[N-(1,3-dihydroxy-2-imidazolidinylidene)-N'-phenylmethanediimine) platinum(II) (L1aPt-b)

The interactions of imidazolidine and thiazolidine-based isatin derivatives (IST-01 to 04) with ds-DNA have been reported by Nasima Arshad et al. Among all compounds tested at physiological pH and temperature (7.4, 37 ◦C), the evaluated binding parameters—binding constant (Kb), free energy change (∆G), and binding site sizes (n)—inferred that IST-02 and IST-04 had relatively greater and more spontaneous binding interactions with the DNA. With percentage cell toxicity of IST-02 and IST-04 is 70% and 66%, respectively, at 500 ng/µL dosage, were found to be the most cytotoxic of all the compounds against HuH-7 cell lines. Thus, imidazolidine (Z)-Ethyl 2-(3-((1-benzyl-5-chloro-2-oxoindolin-3-ylidene)amino)-4-oxo-2-thioxoimidazolidin-1-yl)acetate (IST-02) and thiazolidine (IST-04)-based isatin derivatives were demonstrated to be effective anticancer drug candidates in both DNA binding and cytotoxicity studies (Figure 3). The imidazolidine IST-02 compound shows the most promising anticancer activity⁶.

Figure No. 3: Chemical structure of imidazolidine (Z)-Ethyl 2-(3-((1-benzyl-5-chloro-2-oxoindolin-3-ylidene) amino)-4-oxo-2-thioxoimidazolidin-1-yl) acetate

Tao Liang et al investigated the therapeutic effect and low toxicity of HDAC6 isoform-selective inhibitors making them a viable substitute for pan-HDAC inhibitors. The strongest compound 4-((4-benzyl-2,5-dioxo-3-(pyridine-3-yl methyl) imidazolium-1-yl)methyl)-N-hydroxy benzamide, demonstrated selectivity that was 5545-fold, 5864-fold, and 1638-fold greater than that of HDAC1, HDAC2, and HDAC8, respectively, and had a low nanomolar HDAC6 inhibitory activity (IC₅₀ ¼ 2.1 nM) (Figure 4). Compound 71 selectively raised the acetylation level of a-tubulin without altering histone H3, according to additional confirmation from Western blot analysis. Additionally, compound 71 exhibits favorable characteristics in terms of cytotoxicity, anti-proliferative activity, apoptosis induction, caspase-3 activation, and plasma stability. As a result, compound 71 can be used as a lead compound to create a more powerful HDAC6 selective inhibitor or in cancer treatment. The strongest molecule, compound 71, exhibits enhanced selectivity against HDAC1, HDAC2, and HDAC8, respectively, and a low nanomolar inhibitor activity for HDAC6 (IC₅₀ ¼ 2.1 nM).Additionally, compound 71 has favorable qualities in terms of cytotoxicity, plasma stability, and anti-proliferative effects⁷.

Figure No. 4: Chemical Structure of 4-((4-benzyl-2,5-dioxo-3-(pyridine-3-yl methyl) imidazolium-1-yl)methyl)-N-hydroxy benzamide

Faez AA et al prepared a novel heterocyclic imidazoline-4-one derivative, 2-hydroxy-5-((4-nitrophenyl)diazenyl) benzaldehyde (F1) is the first step. Imidazolodine-2-one derivative 5-((1H-indol-3-yl)methyl)-2-(2-hydroxy-5-((4-nitrophenyl)diazenyl) phenyl)-3-(5-mercapto-1,3,4-thiadiazol-2-yl) imidazoline-4-one (F2) was synthesized and identified in this work from the Schiff base derivative (F1) (Figure 5). These substances were identified using the proton nuclear magnetic resonance (1H-NMR) spectrum and Fourier-transform infrared spectroscopy (FTIR). The anticancer potential of the imidazolidine derivative F2 against the LS-174T cell line may be somewhat comparable to that of DOX and 5-FU, with dose-dependent values of 0.7436, 0.7662, and 0.7653, respectively, and IC₅₀ values of 54.406, 63.140, and 55.006, respectively⁸.

Figure No. 5: Chemical structure of 2-hydroxy-5-((4-nitrophenyl)diazenyl) benzaldehyde

Al-Harbi RAK et al produced imidazopyrazine and imidazolidine derivatives when imidazolidineiminothiones reacted with certain amino acids methyl ester (Figure 6). Compound 1-(4-Chlorophenyl)-6-(4-hydroxyphenyl)-3-(4-iodophenyl)-1H-imidazo[4,5-b]pyrazine2,5(3H,6H)-dione (5a), which contains an imidazo[4,5-b]pyrazine-2,5-dione moiety substituted at positions 1, 3, and 6 with 4-chlorophenyl, 4-iodophenyl, and 4-hydroxyphenyl moieties, exhibited the highest cytotoxic activity among the products that were synthesized using nanotechnology. Its IC₅₀ values against the MCF-7, HCT-116, and HEPG-2 cell lines were lower than those of the reference medication. For HEPG-2, HCT-116, and MCF-7, the corresponding IC₅₀ values of compound 5a were 5.02, 4.91, and 4.78 μM, respectively; for doxorubicin, they were 7.46, 8.29, and 4.56 μM, respectively⁹.

Figure No. 6: Chemical structure of 1-(4-Chlorophenyl)-6-(4-hydroxyphenyl)-3-(4-iodophenyl)-1H-imidazo[4,5-b] pyrazine 2, 5(3H, 6H)- dione (5a)

Anti-proliferative activity:

Hassan et al have reported that 3-substituted-1-[2-(5)-3-substituted-4-benzyl-5-oxo-4-phenyl-2-thioxoimidazolidin-1-yl] has two enantiomers, (R) and (S).The diastereoselective reaction between N,N``-1,ω-alkanediylbis[N}-organylthiourea] derivatives and 2,3-diphenylcyclopropenone in refluxing ethanol produced ethyl/propyl-5-benzyl-5-phenyl-2-thioxoimidazolidin-4-ones. Mass spectra, NMR, IR, and elemental analyses were used to validate the structures of the isolated compounds. Furthermore, the structure of the isolated compounds was also clarified using single-crystal X-ray structure analysis. Comparing the tested compounds to erlotinib as a reference, which has an IC₅₀ value of 70 nM, revealed EGFR inhibitory activity with IC₅₀ values ranging from 90 nM to 178 nM. The most powerful anti-proliferative was discovered to be compound (R)-3-Allyl-1-[3-(S)-3-allyl-4-benzyl-5-oxo-4-phenyl-2-thioxoimidazolidin-1-yl) propyl)-5-benzyl-5-phenyl-2-thioxoimidazoline-4-one (4c), which had the highest inhibitory effect on EGFR with an IC₅₀ value of 90 nM as opposed to 70 nM for erlotinib¹⁰(Figure 7).

Figure No. 7: Chemical structure of (R)-3-Allyl-1-[3-(S)-3-allyl-4-benzyl-5-oxo-4-phenyl-2-thioxoimidazolidin-1-yl) propyl)-5-benzyl-5-phenyl-2-thioxoimidazoline-4-one (4c)

Anti-psychotropic activity

Walid Guerrab et al synthesized 3-decyl-5,5-diphenylimidazolidine-2,4-dione (Figure 8). The highest affinity value of approximately 7.9 kcal/mol was found for the suggested binding mode of 3DDID with the GABA-A receptor. Therefore, compound 3DDID's hydrophobic interaction could account for its high binding free energy and psychotropic activity when compared to phenytoin and diazepam. Consequently, it has the highest neuro-pharmacological activity when compared to phenytoin and diazepam¹¹.

Figure No. 8: Chemical structure of 3-decyl-5,5-diphenylimidazolidine-2,4-dione

Anti-convulsant activity

Rohit Jaysing Bhor et al. synthesized 1-acetyl-3-(2-aminophenyl)-5,5-diphenylimidazolidine-2,4-dione derivatives(SA4) were synthesized as a structural homolog of phenytoin and showed promise as anticonvulsants(Figure 9). The most potent of all the synthesized compounds was found to be compound SA4 which had the highest docking score (-6.33).The synthesized compound was found to have good potential antiepileptic properties, acting primarily through the mechanism of action of traditional medications such as phenytoin. Furthermore, when the synthetic compounds dock with the voltage-gated calcium channel receptor, they seem to exhibit potent anticonvulsant effects.¹²

Figure No. 9: Chemical structure of 1-acetyl-3-(2-aminophenyl)-5,5-diphenylimidazolidine-2,4-dione derivatives(SA4)

By alkylating the parent spiro hydantoin (spiro[fluorene-9,4'-imidazolidine]-2',5'-dione) 2 by heating 9-fluorenone 1 with potassium cyanide and anhydrous ammonium carbonate under the guidance of the Bucherer-Bergs reaction, thiazolidinediones (hydantoins) (3a-e) were produced with good yield by Marzouk AA et al (Figure 10). According to the preliminary anticonvulsant assessment, every compound worked well for s.c.Pentylenetetrazolescreening. Compound Ethyl 6-(2ʹ,5ʹ-dioxospiro[fluorene-9,4ʹ-imidazolidine]-1ʹ-yl)hexanoate (3d) demonstrated 100% protection against s.c.Pentylenetetrazole-induced seizures in the imidazolidinedione series I (3a–e), demonstrated greater potency than the reference medication valproate sodium, which only achieved 83.33% protection at the same dosage level. In contrast, compound 3b demonstrated the highest level of protection of 83.33% when used as a reference medication for valproate sodium. According to the results, compound 3d, which is connected to the thiazolidinedione nucleolus by a longer aliphatic side chain (n=5), demonstrated 100% protection against s.c.Pentylenetetrazolecaused seizures. The results of the rotarod test showed that nearly all of the compounds were not neurotoxic. Various spectrometric techniques and elemental analysis characterized the target compounds' chemical structures¹³.

Figure No. 10: Chemical structure of Ethyl 6-(2ʹ,5ʹ-dioxospiro[fluorene-9,4ʹ-imidazolidine]-1ʹ-yl) hexanoate

Anti-arrhythmic activity:

The class of LCAPs derivatives includes the tested compounds 10 and 5-Methyl-5-phenyl-3-[3-(4-(2-methoxyphenyl) piperazin-1-yl)propyl]-imidazolidine-2,4-dione, as well as the reference medication urapidil (6-({3-[4-(2-methoxyphen-yl)piperazin-1-yl]propyl}amino)-1,3-dimethylpyr-imidine-2,4(1H,3H)-dione) (Figure 11). As an α1-adrenolytic, urapidil lowers blood pressure and stops the anticipated reflex increase in sympathetic nerve activity, according to pharmacological theory. Urapidil dramatically reduced the incidence of ventricular tachycardia and ventricular fibrillation in the isolated rat heart in the earlier studies (30–32) at concentrations of 10–6M.Furthermore, following intravenous administration, urapidil demonstrated a strong preventive and therapeutic antiarrhythmic effect in adrenaline-induced arrhythmia, with ED50 values of 1.26 and 3.4 mg/kg, respectively. The antiarrhythmic activity of novel aminoalkyl derivatives with imidazo[2,1-f]purine-2,4-dione (10) and imidazolidine-2,4-dione (12) cores may be linked to their α1-adrenolytic properties, according to their pharmacological results¹⁴.

Figure No. 11: Chemical structure of 5-Methyl-5-phenyl-3-[3-(4-(2-methoxyphenyl) piperazine-1-yl)propyl]-imidazolidine-2,4-dione

Antimicrobial activity

Mogle PP et al synthesized 2-isonicotinoyl-4,6-dihydroimidazo[4,5-c] pyrazole-5 (2H)-one derivative (4a-i) using a single pot and a three-component combination of substituted aromatic aldehyde (1a-i), imidazolidine-2,4-dione (2), and isonicotinic acid hydrazide (3), added one at a time in the environmentally friendly solvent PEG-400 while stirring at 60–70 °C for three to four hours with a catalytic amount of BEC (pH 12.5, 10wt%) acting as a promotor (Figure 12). Dihydroimidazo's antifungal activity was assessed [4,5-c]. The three fungal strains Aspergillus niger, Aspergillus flavus, and Penicillium citrinum, using derivatives of pyrazol-5 (2H)-one. All fungal strains are susceptible to the promising antifungal activity of compounds 4a, 4b, 4d, 4e, 4h, and 4i.The compounds 4a, 4b, 4d, 4e, 4h, and 4i demonstrated good antifungal activity against the utilized fungal strains Penicillium citrinum, Aspergillus niger, and Aspergillus flavus, according to the results. Which discovered that 4-chlorophenyl compound 3Dihydroimidazo-2-isonicotinoyl-4,6-[4,5-c] Pyrazole-5 (2H) With a binding energy of -10.0 kcal/mol against the Trypanosoma cruzienzyme PDB:3KHM, one showed the highest docking score¹⁵.

Figure No. 12: Chemical structure of 2-isonicotinoyl-4,6-dihydroimidazo[4,5-c] pyrazole-5(2H)-one

By reacting 2(methylthio)-3,5-dihydro-4H-imidazol-4-onederivatives (1a-c) with a few active methylene reagents and nitrogen nucleophiles, we were able to create twenty new imidazolidinone derivatives for this investigation. FT-IR, ¹H NMR, 13C NMR, and Mass spectral analyses were used to confirm the synthesized compounds. Additionally, the DFT/B3LYP/6-31(G) basis set was used to optimize the synthesized compounds and examine their energies as well as the existence of two isomer forms (E and Z). The E form's stability was validated by the results. Additionally, the antimicrobial activity of novel compounds against Aspergillus Nigar, Staphylococcus aureus, Streptococcus mutans, Candida albicans, Escherichia coli and Klebsiella pneumonia were assessed using the inhibition zone technique. Compound Benzyl-5-(piperidin-1-ylmethyl)-2-thioxo imidazolidin-4-one (11c) contains a piperazine moiety outside the plane of the benzene ring, the results show that it exhibited higher activity than other compounds (Figure 13). Twenty new imidazolidinone derivatives were created for this investigation and their antibacterial and antifungal properties were assessed. Docking analysis confirmed that compound 11c exhibited high activity. Additionally, the presence of the E form of the majority of compounds was confirmed by theoretical analysis. These compounds' lipophilicity, which can be used in numerous biological studies and be active at varying doses was demonstrated by their ADMET studies¹⁶.

Figure No. 13:Chemical structure ofBenzyl-5-(piperidine-1-ylmethyl)-2-thioxo imidazolinium-4-one

Hussein Ali Qabel et al synthesized the derivatives of 4-oxazolidine, 4-imidazolidine, and 4-thiazoline from prednisone. The substances are tested against both Gram-positive and Gram-negative bacteria, including Escherichia coli and Staphylococcus aureus. The antibiotic Ceftriaxone was used as a positive control at a concentration of (100 μg/mL). According to the antibacterial activity results, the compounds (8–14) and (16–18) that were tested had the strongest antibacterial activity against Staphylococcus aureus. The compounds that were tested (8, 9, 13, 15, 16, and 17) demonstrated the strongest antibacterial activity against Escherichia coli, according to the antibacterial activity results. Although compounds (9–20) exhibited lethal inhibition and are the most powerful, their antifungal (Candida) activity was found to be higher than that of conventional medications. Compounds 8, 1-Phenyl-2-glycyl-[((4-methoxyphenyl)-imidazolidin-4-one-3-yl)-3-pyrazolidinone-2-yl] (9) and 14 among the recently synthesized uracil derivatives exhibit exceptionally high antioxidant capacity and efficiently convert Mo (VI) to Mo (V) at concentrations of 50, 100, and 150 µg/mL (Figure 14). In the reducing power assay, compounds 8, 9, 13, 14, and 20 performed better than the standard activity. Furthermore, the findings demonstrated that compounds 8, 9, and 14 exhibited strong antioxidant activity. Compound 9 is more potent due to the presence of methoxy (-OCH3) group which enhances its biological efficacy¹⁷.

Figure No. 14: Chemical structure of 1-Phenyl-2-glycyl-[((4-methoxyphenyl)-imidazoline-4-one-3-yl)-3-pyrazolidinone-2-yl]

Intriguingly, compound carboxamides had therapeutic ratios of 32 and 16 against CaCo cell lines, respectively, according to a toxicity study. Given that antibacterial drug candidates should have antibacterial activity that is more than ten times greater than cytotoxicity, this was a promising place to start. Although it was much less effective than that of the C7-adamantyl carboxamide-N, O-bicyclic tetra mates, which usually had MICs of 0.25 μg mL^-1, C5-carboxamide 23b demonstrated good bioactivity against methicillin-resistant Staphylococcus aureus (MRSA) at MIC = 3.9μg mL^-1 and C7-carboxamide 24a demonstrated good antibacterial activity against MRSA (MIC = 3.9μg mL^-1). Compound 23b's high therapeutic index, ideal chemical characteristics and strong antibacterial activity against MRSA (MIC = 3.9µg/mL) ensure efficacy with minimal toxicity¹⁸.

Figure No. 15: Chemical structure of carboxamides

The disk diffusion method was used to test the antibacterial activity of ten newly synthesized molecules with the biological rings of (bis–tris)-imidazolidine (2,4)-dione. Gram negative bacteria like Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli) were used to test these. It appears likely that the compounds, which include rings of the (bis–tris) imidazolidine/thiazolidine (2,4)-dione, have significant antibacterial activity against Gram-negative bacteria based on the biological results obtained from these compounds. The inhibitory region of compound 5,5′-((hexane-1,6-diylbis(oxy))bis(2,1-phenylene)) bis(imidazolidine-2,4-dione) (4a), which contains two imidazolidine 2,4-dione rings, showed a diameter of 27 mm against Gram-negative E. coli bacteria (Figure 16). Among the other compounds, compound 4a exhibits a high score of nearly -7.90 kcal mol−1 for the Gram-negative bacteria E. coli (PDB ID: 1AB4). The best binding affinity, too¹⁹.

Figure No. 16:Chemical structure of 5,5′-((hexane-1,6-diylbis(oxy))bis(2,1-phenylene)) bis(imidazolidine-2,4-dione)

Marwa Abdullah Saleh et al investigated the newly synthesized biological activities of imidazolidine derivatives against two Gram-positive (Streptococcus pyogenes and Staphylococcus aureus) and two Gram-negative (Klebsiella and E. coli) bacteria were identified. When compared to the standard drug, trimethoprim, all of the synthesized compounds III(a–d) show moderate activity on four different types of bacteria; however, Streptococcus pyogenes exhibits the highest activity of these compounds, while E. coli exhibits the lowest activity. The produced compounds were examined using molecular docking to determine their interaction and binding affinity with bacteria. The compounds (2-fluoro-3-(1-(2-(5-hydroxy-1H-indol-3-yl) ethyl)-5-oxoimidazolidin-2-yl) phenyl) boronic acid (Inc) provided the highest docking scores for both gram-negative (Klebsiella and Escherichia coli) and gram-positive bacteria such as Staphylococcus aureus and Streptococcus pyogenes (Figure 17)²⁰.

Figure No. 17: Chemical structure of (2-fluoro-3-(1-(2-(5-hydroxy-1H-indol-3-yl) ethyl)-5-oxoimidazolidin-2-yl) phenyl) boronic acid

The bicyclic phenyls leno hydantoins Hyd20, Hyd21, and Hyd19 With MICs of <7.81, 15.75, and 62.5μg/mL, respectively, only demonstrated potent antibacterial activity against S. aureus ATCC 25923 have been reported by Biljana Smit et al. Considering the impact of bicyclic phenyls leno hydantoins on S. aureus in investigation, it can be noted that these compounds have a stronger antibacterial effect when the imidazole ring is additionally substituted with methyl and an ester group. The most effective phenyls leno hydantoin derivatives for inhibiting the growth of B. animal is subsp. lactis and S. aureus isolate were the annulated bicyclic and tricyclic derivatives. The isolate of S. aureus showed the highest sensitivity to the bicyclic hydantoin derivative5,7a-Dimethyl-1,3-dioxo-5-phenyl selanylmethyl-hexahydro-pyrrolo[1,2-c] imidazole-7-carboxylic acid ethyl ester (Hyd20)²¹.

Figure No. 17: Chemical structure of 5,7a-Dimethyl-1,3-dioxo-5-phenyl selanylmethyl-hexahydro-pyrrolo[1,2-c] imidazole-7-carboxylic acid ethyl ester

Tushar Patel et al used GLIDE for molecular docking and site identification to design several new imidazolidine-2,4-dione compounds. Following synthesis, elemental analysis, FT-IR, LC-MS, and ¹H NMR were used to characterize the compounds. It was discovered that the compounds had a moderate level of activity against M. tuberculosis. By using isoniazid as the reference medication, the anti-TB activity of the compounds was assessed in terms of MIC. The findings imply that compounds 5-((4,4- dimethyl cyclohexyl) methyl)-1-methyl-3-phenyl imidazolidine-2,4-dione (5h) and 5-(Cycloheptylmethyl)-1-methyl-3-phenylimidazolidine-2,4-dione (5k) have strong anti TB properties. Compounds 5 h and 5 k have respective MIC values of 12.5 and 25 mg/mL (Figure 18)²².

Figure No. 18: Chemical structure of compounds 5h and 5k

Layla Adnan AbdulJabar et al created novel eight compounds the 2-thioxo-4-imidazolidinones (5a–h). FT-IR, ¹H-NMR, ¹³C-NMR, mass spectra, and the melting point were used to determine the chemical structures of the compounds. To target their activities, an examination of the antibacterial and antifungal properties was conducted. With similar minimum inhibitory concentrations (MIC) of 25 mg/mL, compound N-(5-(2-((4-chlorophenyl)amino)-2-oxoethyl)-3-cyclohexyl-4-oxo-2-thioxoimidazolidin-1-yl) benzamide demonstrated antibacterial efficacy against Pseudomonas aeruginosa and Staphylococcus aureus (Figure 19). While compounds 5a, 5b, and 5c had a substantial effect on A. niger, compounds 5a-g also had considerable antifungal effects against C. albicans²³.

Figure No. 19: Chemical structure of N-(5-(2-((4-chlorophenyl)amino)-2-oxoethyl)-3-cyclohexyl-4-oxo-2-thioxoimidazolidin-1-yl) benzamide

Marinova P et al investigated that microorganisms were strongly inhibited by compound 1,3-Dihydroxymethyl-(9'-fluorene)-spiro-5-hydantoin (L1) (inhibition zone 12–17 mm). 4'-Bromo-(9'-fluorene)-spiro-5-hydantoin (L2) demonstrated strong activity against B. subtilis (inhibition zone 18/18 mm), P. aeruginosa (inhibition zone 12/7 mm), S. aureus (inhibition zone 10/10 mm), and Candida albicans (inhibition zone 10/9 mm) (Figure 20). Compound L1 results indicated that it possesses the ability to function as an antimicrobial agent against both Gram-positive and Gram-negative bacteria and yeasts. Compound L2 may be used as an antimicrobial agent against P. aeruginosa, C. albicans, and Gram-positive bacteria. The WST-1 assay results show that the investigated compound L1 and its Cu(II) complex have a cytotoxic effect on human melanoma A2058 cells that is dependent on both concentration and time²⁴.

Figure No. 20: Chemical structure of compounds L1 and L2

Ibrahim TS et al synthesized novel 5-(substituted quinoline-3-yl or 1-naphthyl) methylene)-3-substituted imidazolinium-2,4-dione compounds (9–26). 1H NMR, 13C NMR, and elemental analyses were used to identify the produced compounds. Similar to compound IV, compound (Z)-3-benzyl-5-((2-chloro-8- methyl quinolin-3-yl)methylene)imidazolidine-2,4-dione is the most effective at preventing HIV-1IIIB infection (Figure 21). The imidazolidine-2,4-dione ring and LYS574 exhibited hydrogen bonding interactions that were overlooked in the weakly active derivatives, according to molecular docking analysis of the novel compounds. The findings showed that the majority of the novel compounds could, in a dose-dependent manner, significantly inhibit HIV-1IIIB replication. Compound 13 was the most effective of the new derivatives in preventing HIV-1IIIB infection, with an EC50 value of 0.148 µM and a selectivity index of 117.36. Compound 13 demonstrated an EC50 value of 8.7 µM against 92US657 (R5, Clade B), the primary HIV-1 isolate²⁵.

Figure No. 21: Chemical structure of (Z)-3-benzyl-5-((2-chloro-8- methyl quinolin-3-yl)methylene)imidazolidine-2,4-dione

Imidazolidine-2,4-dione compounds 3a–h are a new class of compounds that have been successfully synthesized and characterized by Daoud Ali et al. All compounds have antimicrobial activity, according to the antimicrobial activity screening. Compound (Z)-5-(4-bromobenzylidene)-3-((Z)-((E)-3-phenyl allylidene)amino)imidazolidine-2,4-dioneexhibits greater activity (MIC: 0.25g/mL) against both pathogens (Figure 22). The potential bacterial activity was demonstrated by compound 3g with a 4-Br halogen group on the phenyl with imidazoline-2,4-dione. When compared to Ciprofloxacin (MIC: 0.5g/mL), compound 3g has equipotential (MIC: 0.5g/mL) and high (MIC: 2g/mL) activity against S. aureus and E. faecalis. This is because both standard and compound 3g have halogen groups, which give them equal activity against S. aureus species. Mass spectra, 1H, 13CNMR, and FT-IR were utilized to conform new molecules and assess their anti-microbial activity²⁶.

Figure No. 22: Chemical structure of (Z)-5-(4-bromobenzylidene)-3-((Z)-((E)-3-phenyl allylidene)amino)imidazolidine-2,4-dione

12. Marin Marinov et al., The heterocyclic compounds imidazolidine-2,4-diones (spiro hydantoins and hydantoins) and nalidixic acid (1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid) have nitrogen atoms in their rings. Nalidixic acid's interaction with spirohydantoins serves as the basis for the synthesis of naphthyridine compounds 4a–4i. The compounds' effects were most noticeable on the Gram-positive Bacillus subtilis bacteria, where the zones of growth inhibition ranged from 26.3 mm compound 8-ethyl-3-(1-ethyl-7-methyl-4-oxo-1,4-dihydro-1, 8-naphthyridine-3-carbonyl)-1,3-diazaspiro [4.5] decane-2,4-dione(4f) to 28 mm compound 3-(1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine- 3-carbonyl)-1,3-diazaspiro[4.5] decane-2,4-dione(4b) (Figure 23). IR, 1 H, 13C NMR spectral data, elemental analysis, and physic-chemical parameters are used to demonstrate the structures of the compounds that were obtained. These compounds have strong antibacterial pharmacological activity. In addition, aldose reductase inhibitors and antifungal drugs²⁷.

Figure No. 23: Chemical structure of compounds 4b and 4f

Antibiotic resistance is becoming one of the most significant public health issues. By mimicking the key physiochemical characteristics of host-defense peptides (HDPs), a series of imidazolidine-4-one derivatives with strong, broad-spectrum antibacterial activity and a low rate of drug resistance were created in an attempt to fight bacterial infections. Both Gram-positive and Gram-negative bacteria, including several strains of bacteria resistant to multiple drugs, were effectively combatted by these tiny molecules. The most effective compound N,N'-((2S,2'S)-((1,4-phenylene bis(4-oxoimidazolidine-3,1-diyl)) bis(6-aminohexane-1,2-diyl))bis(decanamide) (3), was found to be able to both quickly eradicate the bacteria and show a low likelihood of drug resistance in MRSA across numerous passages, according to time-kill kinetics and drug resistance studies (Figure 24). According to additional mechanistic research, three eliminated bacterial pathogens by breaking down the membranes of both Gram-positive and Gram-negative bacteria. The activity significantly improved when the alkyl chains' carbon count reached ten for compound 3²⁸.

Figure No. 24: Chemical structure of N, N'-((2S,2'S)-((1,4-phenylene bis(4-oxoimidazolidine-3,1-diyl)) bis(6-aminohexane-1,2-diyl))bis(decanamide)

Angelova VT et al using Knoevenagel condensation, new hydantoin and thiazolidinedione derivatives were produced in good yields. The spectral data was used to assign the structures. The target molecules exhibit anti-TB activity, according to the assay results, and the hydantoin derivatives (5Z)-5-(5-benzyloxy-3-indolylmethylene)-1,3-imidazolidine-2,4-dione are more active than their thiazolidinedione counterparts (Figure 25). The compounds are selective for M. tuberculosis, as evidenced by their low cytotoxicity against the human embryonic kidney cell line HEK-293. The majority of them seem to be possible inhibitors of specific cytochrome P450 enzyme isoforms. Both have exhibited encouraging outcomes. Some of the most potent compounds in the series had docking scores of –7.67 (the highest value ever recorded) and –7.15, respectively²⁹.

Figure No. 25: Chemical structure of (5Z)-5-(5-benzyloxy-3-indolylmethylene)-1,3-imidazolidine-2,4-dione

Anti-plasmodial activity:

The creation and initial physicochemical analysis of new bioinspired thiazolidinedione derivatives, in which the basic piperazine component and the alkylene chain connected the thiazolidinedione core to the bicyclic system. The chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of P. falciparum were used to test these compounds against their asexual stages. The findings showed that the W2 strain was more susceptible to the antiplasmodial effects than the D10 strain (6202.00–9659.70 ng/mL (12.75–19.85 µM)), with an IC₅₀ ranging from 2424.15 to 5648.07 ng/mL (4.98–11.95 µM). At a concentration that was active against the parasite but not harmful to mammalian cell lines, these molecules were also non-hemolytic to human erythrocytes. The synthesized derivatives seem like promising antimalarial medication candidates because of their increased antimalarial activity against the CQ-resistant strain of P. falciparum. Racemic compounds (5–8) were produced by coupling intermediates (3 or 4) with corresponding arylpiperazines, specifically 1-(2,3-dihydro-1H-inden-2-yl)piperazine or 2-(piperazin-1-yl)-1Hbenzo[d]imidazole, whose analytical results were consistent with previously reported protocols. Due to its low toxicity to mammalian cells and highest activity against P. falciparum strains, particularly the CQ-resistant strain, compound (R,S)-1-(5-(4-(1H-Benzo[d]imidazol-2-yl) piperazine-1-yl)pentyl)-30,40-dihydro-20H-spiro[imidazolidine-4,10-naphthalene]-2,5-dione (5) proved to be the series' best-hit compound (Figure 26). Owing to its poor water solubility, compound 5 was demonstrated to induce only mild hemolysis at a concentration of 5.6%, which is equivalent to 3.2-fold (D10) and 8.2-fold (W2) of the IC₅₀ of the corresponding Plasmodium strains³⁰.

Figure No. 26: Chemical structure of (R, S)-1-(5-(4-(1H-Benzo[d]imidazol-2-yl) piperazine-1-yl)pentyl)-30,40-dihydro-20H-spiro[imidazolidine-4,10-naphthalene]-2,5-dione

CONCLUSION:

An examination of the literature indicates that imidazolidine and its derivatives are a significant class of compounds in the medicinal field including anti-cancer, anti-psychotropic, anti-convulsant, anti-arrhythmic, anti-microbial, and anti-plasmodial properties. The observed biological activities and unique chemical properties make the researchers useful for further research and development. These highly active imidazolidine derivatives may be used to discover new products with potential medical uses in the future.

CONFLICT OF INTEREST:

The authors declare no conflicts of interest regarding this review article.

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Received on 30.12.2024 Revised on 16.01.2025

Accepted on 30.01.2025 Published on 24.02.2025

Available online from February 27, 2025

Asian J. Research Chem.2025; 18(1):41-51.

DOI: 10.52711/0974-4150.2025.00008

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