Skip to main content
NCBI home page
ACS Omega logoLink to ACS Omega
. 2023 Nov 10;8(46):44312–44327. doi: 10.1021/acsomega.3c07125

Novel Scaffolds Based on Bis-thiazole Connected to Quinoxaline or Thienothiophene through 2-Phenoxy-N-arylacetamide Groups as New Hybrid Molecules: Synthesis, Antibacterial Activity, and Molecular Docking Investigations

Mostafa E Salem †,‡, Abbas H Abdullah ‡, Nada S Ibrahim §, Magdi E A Zaki †, Ahmed H M Elwahy ‡,*, Ismail A Abdelhamid ‡,*
PMCID: PMC10666262  PMID: 38027350

Abstract

graphic file with name ao3c07125_0014.jpg

The resistance of microorganisms to antimicrobials has endangered the health of many people across the world. Overcoming the resistance problem will require the invention of molecules with a new mechanism of action so that no cross-resistance with existing therapies occurs. Because of their powerful antibacterial activity against a wide spectrum of Gram-positive and Gram-negative bacterial strains, heterocyclic compounds are appealing candidates for medicinal chemists. In this regard, as unique hybrid compounds, we synthesized a novel family of bis-thiazoles linked to quinoxaline or thienothiophene via the 2-phenoxy-N-arylacetamide moiety. The target compounds were synthesized by reacting the relevant bis(α-haloketones) with the corresponding thiosemicarbazones in EtOH at reflux with a few drops of TEA. Under comparable reaction conditions, the isomeric bis(thiazoles) were synthesized by reacting the appropriate bis(thiosemicarbazone) with the respective α-haloketones. The structures of the novel compounds were confirmed using elements and spectral data. All of the synthesized compounds were tested for antibacterial activity in vitro. With an inhibitory zone width of 12 mm, compound 12a had the same activity as the reference medication tobramycin against Staphylococcus aureus. Compound 12b showed 20 mg/mL as a minimum inhibitory concentration (MIC) against Bacillus subtilis. Some of the synthesized compounds were tested via molecular docking against two bacterial proteins (dihydrofolate reductase and tyrosyl-tRNA synthetase).

1. Introduction

The creation of novel antimicrobial medicines has become a hot issue and one of the most difficult problems, while multidrug-resistant bacteria threaten all fields of human medicine worldwide. This involves creating analogues of existing antibacterial medication classes with novel modes of action aiming at increasing potency, reducing resistance, and reducing toxicity.1 The problem of bacterial infection management cannot be dismissed simply by discussing the diseases caused, the bacteria involved, and the benefits and drawbacks of the various antibacterial agents now available, especially since the latter still have certain definite shortcomings. A deeper knowledge of how humans fight and harbor germs, as well as some of the mechanisms by which bacteria create negative consequences, can help with the management of more complex and resistant bacterial illnesses.2 Extensive research has been carried out over the years in the hunt for effective and safe antimicrobial drugs based on heterocyclic scaffolds, particularly to combat the ever-increasing microbial resistance and to minimize the high late-stage attrition rate in the drug development process. In this regard, thiazole derivatives have been shown to exhibit antiviral, antibacterial, antifungal, antidiabetic, antioxidant, anti-inflammatory, anticancer, and analgesic properties.3−9 They are also found in 18 clinically approved drugs (FDA-approved), including antitumor drugs (epothilone and tiazofurin), anti-inflammatory drugs (meloxicam), antifungal drugs (isavuconazole), antiparasitic drugs (thiabendazole and nitazoxanide), antigout drugs (febuxostat), antithrombotic drugs (edoxaban), antiulcer drugs (nizatidine and famotidine), and antibacterial drugs (aztreonam, sulfathiazole, cefepime, and ceftriaxone) (Figure 1).10−12 Because of the simplicity of chemical achievement as well as structural optimization, thiazole-based scaffolds are the most attractive heterocycles in synthetic medicinal chemistry.6,13,14 Furthermore, phenoxyacetamide and its derivatives are pharmacologically active molecules with anticancer, antiviral, antioxidant, anti-inflammatory, antiparasitic, antibacterial, and antihyperglycemic effects, as well as antituberculosis and MAO-A inhibitor activity.15−23 AdipoRon VI (Figure 1), a phenoxyacetamide medication, has received a lot of interest in this respect as a potential therapy for obesity, cardiovascular disease, diabetes, and nonalcoholic fatty liver disease. Moreover, quinoxaline derivatives have been the focus of substantial investigation since they have emerged as an important heterocyclic moiety with a varied spectrum of physicochemical and biological functions including antibacterial, antitubercular, antimalarial, antiviral, anti-inflammatory, antifungal, anticancer, antiproliferative, antitumor, and anticonvulsant properties.24−34 They have a wide variety of biological actions. Figure 1 depicts the quinoxaline core structure of several pharmacological compounds.35 In addition to the prospective applications of thieno[2,3-b]thiophene derivatives in optical and electrical systems, they have also sparked significant medicinal interest due to their diverse biological properties, which include antibacterial, antiviral, anticancer, and antiglaucoma properties.36−45 Furthermore, bis-heterocyclic compounds are widely used as scaffolds in drugs and pharmaceutically relevant substances. Many bis-heterocycles have been shown to have anticancer, antibacterial, antiallergic, and other disease-fighting characteristics when linked properly.46,47 Molecular hybridization is the process of combining at least two pharmacophore fragments from different bioactive chemicals to create hybrids that outperform the original drugs. The pharmacophore scaffolds of several compounds are combined to create hybrid molecules. In this regard, anticancer drugs that are safer and more effective than those presently on the market may benefit from hybridization.48,49 In light of these findings, as well as our continuing interest in the synthesis of heterocycles50−62 and their bis(heterocycles),63−77 we sought to incorporate N-arylacetamide units into the backbone of thiazole to obtain a novel series of bis-thiazole derivatives linked through biologically active quinoxaline or thienothiophene cores using a “hybrid conjugation of bioactive ligands” approach. Our synthetic strategy employs 2-(4-(1-(2-carbamothioylhydrazineylidene)ethyl)phenoxy)-N-(aryl)acetamides, 2-(4-(2-bromoacetyl)phenoxy)-N-(aryl)acetamides, bis(4,1-phenylene)bis(2-bromoethan-1-ones) 7, bis(α-bromoketone), and bis(thiosemicarbazone) as precursors (Figure 2).

Figure 1.

Figure 1

Open in a new tab

Some clinically approved drugs (FDA-approved) include the thiazole ring, quinoxline, or the phenoxyacetamide moiety.

Figure 2.

Figure 2

Open in a new tab

Design concept of bis-thiazole derivatives.

2. Results and Discussion

2.1. Synthesis

In boiling DMF, the potassium salt of 4-hydroxyacetophenone (2) reacts with the corresponding 2-chloro-N-arylacetamide derivatives (1a,b) to give the corresponding 2-(4-acetylphenoxy)-N-(aryl)acetamides 3a,b. Bromoacetyl derivatives 6a,b were produced by treating the corresponding 3a,b with N-bromosuccinimide (NBS) in the presence of p-toluenesulfonic acid (p-TsOH). Thiosemicarbazone precursors 5a,b were produced when 3a,b was condensed with one equivalent of thiosemicarbazide (4) in refluxing ethanol acidified with acetic acid (Scheme 1).

Scheme 1. Synthesis of Acetyl-, Bromoacetyl-, and Thiosemicarbazone Derivatives.

Scheme 1

Open in a new tab

Utilizing thiosemicarbazones 5a,b, we investigated the synthesis of bis(thiazoles) 7a,b that are linked to the quinoxaline core to achieve the concept of molecular hybridization. Thus, the reaction of bis(α-bromoketone) 7(78) with the corresponding thiosemicarbazones 5a,b in EtOH at reflux with a few drops of TEA as a catalyst resulted in the novel bis-thiazoles 8a,b in 74 and 76% yields, respectively (Scheme 2).

Scheme 2. Synthesis of Bis-thiazoles 8a,b Linked to the Quinoxaline Core.

Scheme 2

Open in a new tab

The novel isomeric bis(thiazoles) 10a and 10b were successfully synthesized in 77 and 79% yields, respectively, by reacting bis(thiosemicarbazone) 9(78) with the appropriate α-bromoketones 6a and 6b in ethanol at reflux with a few drops of TEA (Scheme 3).

Scheme 3. Synthesis of Isomeric Bis-thiazoles 10a,b Linked to the Quinoxaline Core.

Scheme 3

Open in a new tab

Our investigation was expanded to include the synthesis of novel bis(thiazole) 12a,b linked to the thienothiophene core, in addition to their prospective applications in optical and electrical systems. Thus, the reaction of bis(α-bromoketone) 11(79) with the corresponding thiosemicarbazones 5a,b in refluxing ethanol and a catalytic amount of triethylamine yielded the expected bis-thiazole derivatives 12a,b in good yields (Scheme 4).

Scheme 4. Synthesis of Bis-thiazoles 12a,b Linked to the Thiophene Core.

Scheme 4

Open in a new tab

Similarly, the reaction of bis(thiosemicarbazone) 13(79) with the appropriate α-bromoketones 6a and 6b in ethanol at reflux with catalytic trimethylamine as a basic catalyst yielded bis-thiazoles 14a and 14b in 69 and 73% yields, respectively (Scheme 5).

Scheme 5. Synthesis of Isomeric Bis-thiazoles 14a,b Linked to the Thiophene Core.

Scheme 5

Open in a new tab

We postulated in Scheme 6 that the reaction that culminates in the production of thiazole derivatives begins with the creation of nonisolable intermediates I. Following the loss of water molecules under experimental circumstances, the latter underwent sequential in situ cyclization to yield the appropriate nonisolable intermediates II, which gave the required bis-thiazoles as end condensation products (Scheme 6).

Scheme 6. Plausible Mechanism for the Formation of Targeted Thiazoles.

Scheme 6

Open in a new tab

2.2. Spectroscopy

The proposed structures of the newly synthesized compounds are supported by elemental analyses as well as spectral data. The 1H NMR spectra of 6a revealed the disappearance of the methyl group and the presence of CH2–Br protons, which resonated at 4.82 ppm as singlet signals integrating two protons. Spectroscopic data, such as IR, 1H NMR, and 13C NMR, supported the structure confirmation of thiosemicarbazones 5a,b. C=N stretching was observed in the FTIR range of 1540–1565 cm–1, while the C=S band was discovered between 1212 and 1256 cm–1. C=O stretching was detected between 1710 and 1670 cm–1, and NH stretching was detected between 3225 and 3320 cm–1. As an example, in 1H NMR of 5a, CH2 appeared as a singlet in the range of 4.72–4.74 ppm, while the NH–N signal appeared at 9.98 ppm. At 10.09, however, a broad singlet was observed for NH–C=S. The abovementioned analysis also confirmed the spectral data of the remaining protons, which were found to be in good agreement with the predicted structure. The IR spectrum of 10b revealed an absorption band caused by NH and C=O at 3275 and 1673 cm–1, respectively. Due to D2O-exchangeable NH protons, its 1H NMR spectrum revealed two signals at 10.24 and 11.14 ppm. Furthermore, three distinct singlet signals appear at 2.31, 4.76, and 7.36 ppm, which are attributed to the methyl, methylene ether linkage OCH2CO, and the thiazole ring’s C-5 proton. The chemical shifts and integral values of the remaining protons were all as expected. The mass spectrum of compound 10b revealed a molecular ion peak at m/z 1112 corresponding to its molecular formula.

The IR spectrum of compound 14a revealed the presence of a –NH group absorption band at 3275 cm–1. Furthermore, it displayed C=O values at 1705 and 1681 cm–1. The 1H NMR spectrum of 14a revealed the presence of two singlet signals at 2.25 and 2.80 ppm, which corresponded to four CH3. It also showed ethyl ester as a triplet signal at 1.28 ppm and a quartet signal at 4.34 ppm. It also revealed the OCH2 linkage as a singlet signal at 5.64 ppm. At 10.20 and 11.90 ppm, the two –NH groups appeared as broad signals. The aryl protons were assigned multiplets at 6.91–7.74 ppm.

2.3. Antibacterial Activity

The antibacterial activity of the synthesized compounds was tested against four bacterial strains: two Gram-positive bacteria (Bacillus subtilis (DSM 1088) and Staphylococcus aureus (ATCC 6538) and two Gram-negative bacteria (Pseudomonas aeruginosa (ATCC 10145) and Escherichia coli (ATCC 8739). The antibacterial activity data are shown in Table 1. Compound 12a had a comparable action against S. aureus as the conventional antibiotic tobramycin, with an inhibition zone of 12 mm. Compounds 8a and 12b inhibited S. aureus with an inhibition zone of 11 mm, which was highly similar to tobramycin. When compared to the reference antibiotic clindamycin (the diameter of the inhibition zone was 27 mm), compounds 12a and 12b had modest action against B. subtilis (the diameters of the inhibition zone were 10 and 15 mm, respectively). With a diameter of the inhibition zone of 10 mm, compound 8b had comparable activity to tobramycin (13 mm) and moderate activity to ofloxacin (17 mm) against E. coli. All of the substances tested demonstrated no efficacy against P. aeruginosa. The microdilution technique was performed to determine the minimum inhibitory concentration (MIC) for the most effective compound (12b) which had the highest activity against B. subtilis. MIC is the lowest concentration that inhibits 100% of the bacterial growth. As shown in Figure 3, the MIC was 20 mg/mL for compound 12b.

Table 1. Antibacterial Activity of the Prepared Compounds at a Concentration of 20 mg/mLa.

  diameter of the zone of inhibition (mm) at 20 mg/mL
sample B. subtilis S. aureus P. aeruginosa E. coli
8a NA 11 NA NA
8b NA NA NA 10
10a NA NA NA NA
10b NA NA NA NA
12a 10 12 NA NA
12b 15 11 NA NA
14a NA NA NA NA
14b NA NA NA NA
tobramycin80   12   13
ofloxacin81     20 17
clindamycin 27 23    
DMSO 0.0 0.0 0.0 0.0
Open in a new tab
a

Standard antibiotic tobramycin (10 μg) for S. aureus and E. coli, ofloxacin (2 μg/disk) for Gram-negative bacteria, and clindamycin (2 μg/disk) for Gram-positive bacteria. NA: no activity.

Figure 3.

Figure 3

Open in a new tab

Microdilution assay for compound 12b against B. subtilis.

2.4. Structure–Activity Relationship

The location of the bis-thiazoles from the quinoxaline core in derivatives 8a, 8b, 10a, and 10b had a significant influence on activity, according to the structure–activity relationship. Because of the closeness of the bis-thiazoles to the quinoxaline core in derivatives 8a and 8b, they showed promising efficacy against S. aureus and E. coli when compared to tobramycin, respectively. While the presence of bis-thiazoles farther away from the quinoxaline core decreased antibacterial activity in derivatives 10a and 10b, the inclusion of the electron-donating group (methyl) and the electron-withdrawing moiety (Cl) in derivatives 8a and 8b, respectively, had no discernible effect on activity. Similarly, in derivatives 12a and 12b, the presence of bis-thiazoles close to the thiophene core resulted in promising action against S. aureus and slight activity against B. subtilis when compared to tobramycin and clindamycin, respectively. The presence of bis-thiazoles distant from the thienothiophene core in derivatives 14a and 14b reduced activity. The activity of derivatives 12a and 12b differed little depending on whether the methyl group or the Cl atom was present.

2.5. Molecular Docking

The molecular docking study was carried out to evaluate the potential mechanism of action of compounds 8a, 8b, 12a, and 12b as antibacterial agents. For this investigation, bacterial dihydrofolate reductase (DHFR) and tyrosyl-tRNA synthetase (TyrRS) were used. The enzyme DHFR is involved in the folic acid pathway.82 It converts dihydrofolate to tetrahydrofolate, boosting thymidylate production, DNA replication, RNA transcription, protein translation, and cell development.83 Other tetrahydrofolate metabolites are also involved in the conversion of single-carbon units into pyrimidines, purines, and amino acids.82 As a result, DHFR suppression can result in a lack of protein and nucleic acid components, resulting in a halt in DNA synthesis and programmed cell death. Aminoacyl-tRNA synthetases (aaRSs) are a class of enzymes that promote the transfer of amino acids to their matching tRNAs during protein synthesis.84 Since the identification of this information, which includes the structures of the amino acids and the coinciding tRNA molecules, it is critical to transform the coded information into protein structures in nucleic acids.85 TyrRS belongs to the aaRSs family, which is found in all living organisms and has two highly conserved sequence motifs at the active site, HIGH and KMSKS.84 Compounds 8a, 8b, 12a, and 12b fit in the active site of DHFR with comparable binding energies (−40.8, −37.14, −39.7, and −37.9 kcal/mol) relative to the cocrystallized ligand (−16.2 kcal/mol), as shown in Table 2. Binding energies of our compounds were found to be more negative than those of the standard, implying that they fit with higher stability than the standard. The binding energies for TyrRS were likewise extremely comparable (−36, −36.6, −37.1, and −40 kcal/mol, respectively) and were more negative than the standard (−18.6 kcal/mol) (Table 2). Figure 3 depicts the modes of interaction of the investigated compounds with the DHFR active site. It was found that compound 8a interacted through 11 interactions, one hydrogen bond between the nitrogen of quinoxaline ring and LYS: 144 with bond distance 5.68 A0; two alkyl hydrophobic interactions with VAL: 6 and LYS: 45; seven π-alkyl hydrophobic with ALA: 7, LYS: 29, LEU: 20, LEU: 28, LEU: 54, and LYS: 32 residues; and one unfavorable acceptor–acceptor with SER: 49 (Figures 4a and 5a). Compound 8b was able to fit into the active site of DHFR via 12 interactions, including three hydrogen bonds with LYS: 32, ILE: 50, and LYS: 52; one π-cation electrostatic with LYS: 32; and eight π-alkyl hydrophobic with HIS: 23, PRO: 55, LEU: 28, and LYS: 32 residues (Figures 4b and 5b). Compound 12a had 14 interactions: three hydrogen bonds with GLN: 19, LEU: 20, and LYS: 144; one π-cation electrostatic interaction with LYS: 29; and 10 alkyl and π-alkyl hydrophobic interactions with LYS: 29, LEU: 28, LEU: 54, HIS: 23, LEU: 20, ALA: 7, VAL: 6, and ILE: 14 residues (Figures 4c and 5c). Figures 4d and 5d reveal 11 contacts for compound 12b, including one hydrogen bond with SER 49; one π-cation electrostatic interaction with LYS 23; and nine π-alkyl hydrophobic interactions with VAL 6, ALA 7, ILE 14, LEU 20, ILE 50, LEU 54, and LEU 28 residues. Compound 8a was found to match TyrRS through nine interactions (Figures 6a and 7a). Two hydrogen bonds were formed with LYS: 84 and ASP: 195; five alkyl hydrophobic contacts were formed with ALA: 43, HIS: 47, HIS: 50, TRP: 241, and VAL: 224; one π–π stacked with HIS: 47; and one π–σ with LEU: 223. Figures 6b and 7b show five hydrogen bonds with GLY: 49, ASP: 40, and LYS: 84; two alkyl hydrophobic with CYS: 37 and LEU: 70; two π-alkyl hydrophobic with PRO: 53 and LYS: 84; one π-sulfur between the benzene ring and CYS: 37; and one π-cation electrostatic between the benzene ring and LYS: 84. Compound 12a also had 11 interactions, including three hydrogen bonds with LYS: 84 and ASP: 195; three electrostatic interactions with ASP: 80, LYS: 84, and TRP: 241; and five hydrophobic interactions with HIS: 47, PRO: 53, LEU: 223, ALA: 239, and TRP: 241 residues (Figures 6c and 7c), while compound 12b fitted via 12 interactions, including four hydrogen bonds with HIS: 50 and ASP: 40; two π-cation electrostatic with LYS: 84 and LYS: 234; four alkyl hydrophobic with CYS: 37, LEU: 70, LYS: 84, and LYS: 231; one π–π T-shaped with HIS: 47; and one π-alkyl hydrophobic interaction with LYS: 234 (Figures 6d and 7d). As a result, compounds 8a, 8b, 12a, and 12b may have antibacterial action by inhibiting the bacterial DHFR and TyrRS enzymes.

Table 2. Binding Energy Values for Compounds 8a, 8b, 12a, and 12b and Standard Ligands with Bacterial Dihydrofolate Reductase and Tyrosyl-tRNA Synthetase Proteins.

  Gibbs free energy (S) (kcal/mol)
sample bacterial dihydrofolate reductase bacterial tyrosyl-tRNA synthetase
8a –40.8 –36
8b –37.14 –36.6
12a –39.7 –37.1
12b –37.9 –40
cocrystallized ligand (standard) –16.2 –18.6
Open in a new tab

Figure 4.

Figure 4

Open in a new tab

Two-dimensional (2D) representation of (a) compound 8a, (b) compound 8b, (c) compound 12a, and (d) compound 12b with bacterial dihydrofolate reductase.

Figure 5.

Figure 5

Open in a new tab

Three-dimensional representation (3D) of the molecular interaction of (a) compound 8a, (b) compound 8b, (c) compound 12a, and (d) compound 12b with bacterial dihydrofolate reductase.

Figure 6.

Figure 6

Open in a new tab

Two-dimensional representation of (a) compound 8a, (b) compound 8b, (c) compound 12a, and (d) compound 12b with bacterial tyrosyl-tRNA synthetase.

Figure 7.

Figure 7

Open in a new tab

Three-dimensional representation of the molecular interaction of (a) compound 8a, (b) compound 8b, (c) compound 12a, and (d) compound 12b with bacterial tyrosyl-tRNA synthetase.

3. Conclusions

Bis-thiazoles connected to quinoxaline or thienothiophene via 2-phenoxy-N-arylacetamide were synthesized as novel hybrid compounds. Condensation of bis-thiosemicarbazones or bis(α-haloketones) with a suitable reagent is the key step in our synthetic strategy. The mechanistic routes and chemical structures of all synthesized derivatives were described and validated by using spectrum data. The products were produced in high yields using easily accessible starting ingredients and a straightforward method. Compound 12a had promising antibacterial activity when compared to tobramycin and moderate activity when compared to clindamycin. Compound 12b exerted the highest activity against B. subtilis with a diameter of the inhibitory zone and MIC equaled to 15 mm and 20 mg/mL, respectively. The molecular docking simulation demonstrated that compounds 8a, 8b, 12a, and 12b could fit in the active site of bacterial DHFR and TyrRS with binding energies lower than those of the standard.

4. Experimental Section

4.1. General

4.1.1. Synthesis of Target Molecules

Melting points were determined in open glass capillaries with a Gallenkamp apparatus. Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. The infrared spectra were recorded as potassium bromide disks on a PyeUnicam SP 3-300 and Shimadzu FTIR 8101 infrared spectrophotometer. NMR spectra were recorded on a Varian Mercury VXR-300 NMR spectrometer at 300 MHz (1H NMR) and 75 MHz (13C NMR) using DMSO-d6 as solvent Chemical shifts were reported downfield from TMS (=0) for 1H NMR. For 13C NMR, chemical shifts were reported in the scale relative to the solvent used as an internal reference. Mass spectra (EI) were obtained at 70 eV with a Shimadzu GCMQP 1000 EX spectrometer. Compounds 6a and 6b were prepared as described.86

4.1.2. Synthesis of 2-(4-(1-(2-Carbamothioylhydrazineylidene)ethyl)phenoxy)-N-(aryl)acetamide (5a,b)

To a solution of the acetyl compounds 3a,b (10 mmol) in absolute ethanol (25 mL) containing 1 mL of acetic acid, thiosemicarbazide (4) (10 mmol) was added. The reaction mixture was heated under reflux for 3 h and then allowed to cool. The solid formed was collected by filtration and recrystallized from ethanol/DMF to give 5a,b as a yellow powder.

4.1.3. 2-(4-(1-(2-Carbamothioylhydrazineylidene)ethyl)phenoxy)-N-(p-tolyl)acetamide (5a)

Pale yellow powder, (81% yield), mp. 215–217 °C; IR: (potassium bromide) 3421, 3366 (NH2), 3251 (NH), 1675 (C=O) cm–1; 1H NMR: δ 2.25 (s, 3H, CH3), 2.26 (s, 3H, CH3), 4.72 (s, 2H, OCH2C=O), 6.99 (d, 2H, J = 7.2 Hz, ArH), 7.11 (d, 2H, J = 7.5 Hz, ArH), 7.51 (d, 2H, J = 7.2 Hz, ArH), 7.88–7.91 (m, 2H, ArH), 8.18 (s, 2H, NH2), 9.98 (s, 1H, NH), 10.09 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 17.0, 21.5, 67.3, 114.6, 120.3, 127.3, 128.6, 129.4, 130.6, 136.8, 142.5, 161.1, 162.3, 179.9; MS: m/z (%) 356 (M+). Anal. Calcd. for C18H20N4O2S: C, 60.65; H, 5.66; N, 15.72; S, 8.99. Found: C, 60.62; H, 5.69; N, 15.75; S, 8.96.

4.1.4. 2-(4-(1-(2-Carbamothioylhydrazineylidene)ethyl)phenoxy)-N-(4-chlorophenyl)acetamide (5b)

Pale yellow powder, (80% yield), mp. 220–222 °C; IR: (potassium bromide) 3433, 3361 (NH2), 3257 (NH), 1681 (C=O) cm–1; 1H NMR: δ 2.26 (s, 3H, CH3), 4.74 (s, 2H, OCH2C=O), 6.98 (d, 2H, J = 8.4 Hz, ArH), 7.36 (d, 2H, J = 8.4 Hz, ArH), 7.67 (d, 2H, J = 7.8 Hz, ArH), 7.89 (d, 2H, J = 7.8 Hz, ArH), 8.18 (s, 2H, NH2), 10.06 (s, 1H, NH), 10.21 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 16.8, 67.7, 114.2, 121.7, 126.3, 129.7, 133.2, 137.3, 142.1, 158.1, 166.1, 172.7; MS: m/z (%) 376 (M+). Anal. Calcd. for C17H17ClN4O2S: C, 54.18; H, 4.55; Cl, 9.41; N, 14.87; S, 8.51. Found: C, 54.12; H, 4.59; N, 14.85; S, 8.56.

4.1.5. Synthesis of Bis(thiazoles) Linked to Heteroaromatic Cores 8a,b and 12a,b

A mixture of the appropriate bis-2-bromoethanone derivatives 7 or 11 (1 mmol) and the thiosemicarbazone 5a,b (2 mmol) was dissolved in ethanol (25 mL), TEA (0.2 mL) was added, and the reaction mixture was heated at reflux for 3–5 h. The reaction mixture was then left to cool, and the solid product was filtered off and recrystallized from ethanol/DMF, to afford compounds 8a,b and 12a,b.

4.1.6. 2,2′-(((((((Quinoxaline-2,3-diylbis(oxy))bis(4,1-phenylene))bis(thiazole-4,2-diyl))bis(hydrazin-2-yl-1-ylidene))bis(ethan-1-yl-1-ylidene))bis(4,1-phenylene))bis(oxy))bis(N-(p-tolyl)acetamide) (8a)

Brown powder, (74% yield); mp 259–261 °C; IR (KBr): 3311 (NH), 1673 (C=O), 1555 (C=N) cm–1; 1H NMR: δ 2.26 (s, 6H, CH3), 2.32 (s, 6H, CH3), 4.73 (s, 4H, OCH2C=O), 7.06 (d, 4H, J = 8.7 Hz, ArH), 7.13 (d, 4H, J = 8.1 Hz, ArH), 7.35 (s, 2H, thiazol-5-H), 7.45 (d, 4H, J = 8.4 Hz, ArH), 7.53 (d, 4H, J = 8.1 Hz, ArH), 7.58–7.78 (m, 8H, ArH), 8.01 (d, 4H, J = 8.4 Hz, ArH), 10.00 (s, 2H, NH), 11.14 (brs, 2H, NH); 13C NMR (75 MHz, DMSO-d6) δ 17.3, 20.0, 68.1, 102.4, 114.5, 120.6, 121.6, 121.9, 127.1, 127.4, 128.7, 129.5, 134.1, 137.0, 141.1, 145.8, 147.4, 152.3, 155.7, 160.5, 161.3, 167.9, 172.1; MS: m/z (%) 1070 (M+). Anal. Calcd. for C60H50N10O6S2: C, 67.27; H, 4.70; N, 13.08; S, 5.99. Found: C, 67.24; H, 4.71; N, 13.05; S, 5.97.

4.1.7. 2,2′-(((((((Quinoxaline-2,3-diylbis(oxy))bis(4,1-phenylene))bis(thiazole-4,2-diyl))bis(hydrazin-2-yl-1-ylidene))bis(ethan-1-yl-1-ylidene))bis(4,1-phenylene))bis(oxy))bis(N-(4-chlorophenyl)acetamide) (8b)

Brown powder, (78% yield); mp 253–255 °C; IR (KBr): 3275 (NH), 1673 (C=O), 1551 (C=N) cm–1; 1H NMR: δ 2.31 (s, 6H, CH3), 4.76 (s, 4H, OCH2C=O), 7.05 (d, 4H, J = 9 Hz, ArH), 7.36 (s, 2H, thiazol-5-H), 7.38 (d, 4H, J = 9 Hz, ArH), 7.45 (d, 4H, J = 8.7 Hz, ArH), 7.55–7.70 (m, 8H, ArH), 7.76 (d, 4H, J = 8.7 Hz, ArH), 8.01 (d, 4H, J = 8.7 Hz, ArH), 10.24 (s, 2H, NH), 11.14 (brs, 2H, NH); 13C NMR (75 MHz, DMSO-d6) δ 14.1, 67.1, 103.9, 114.6, 121.3, 122.0, 126.6, 127.0, 127.2, 127.4, 127.9, 128.7, 131.2, 132.4, 137.0, 137.4, 146.4, 149.3, 149.9, 151.9, 158.4, 166.6, 170.1; MS: m/z (%) 1110 (M+). Anal. Calcd. for C58H44Cl2N10O6S2: C, 62.64; H, 3.99; N, 12.60; S, 5.77. Found: C, 62.62; H, 3.99; N, 12.61; S, 5.75.

4.1.8. Diethyl 3,4-Bis((4-(2-(2-(1-(4-(2-oxo-2-(p-tolylamino)ethoxy)phenyl)ethylidene)hydrazineyl)thiazol-4-yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (12a)

Brown powder, (71% yield); mp 240–242 °C; IR (KBr): 3275 (NH), 1712 (C=O), 1671 (C=O), 1553 (C=N) cm–1; 1H NMR: δ 1.28 (t, 6H, J = 6.9, CH3), 2.25 (s, 6H, CH3), 2.29 (s, 6H, CH3), 4.34 (q, 4H, J = 6.9, CH2), 4.71(s, 4H, OCH2C=O), 5.66 (s, 4H, OCH2), 6.90 (d, 4H, J = 8.4 Hz, ArH), 7.02 (d, 4H, J = 8.1 Hz, ArH), 7.10–7.53 (m, 10H, ArH and thiazol-5-H), 7.66 (d, 4H, J = 8.4 Hz, ArH), 7.71 (d, 4H, J = 8.4 Hz, ArH), 9.98 (s, 2H, NH), 11.00 (brs, 2H, NH); 13C NMR (75 MHz, DMSO-d6) δ 14.7, 19.7, 28.2, 61.3, 67.2, 104.2, 113.2, 114.6, 116.3, 126.3, 126.5, 126.8, 128.2, 128.6, 129.9, 130.2, 134.3, 135.9, 146.9, 152.6, 156.8, 157.6, 160.4, 167.3, 169.7, 173.5; MS: m/z (%) 1252 (M+). Anal. Calcd. for C66H60N8O10S4: C, 63.24; H, 4.82; N, 8.94; S, 10.23. Found: C, 63.22; H, 4.81; N, 8.95; S, 10.21.

4.1.9. Diethyl 3,4-Bis((4-(2-(2-(1-(4-(2-((4-chlorophenyl)amino)-2-oxoethoxy)phenyl)ethylidene)hydrazineyl)thiazol-4-yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (12b)

Brown powder, (71% yield); mp 234–236 °C; IR (KBr): 3275 (NH), 1710 (C=O), 1675 (C=O), 1553 (C=N) cm–1; 1H NMR: δ 1.28 (t, 6H, J = 6.9, CH3), 2.29 (s, 6H, CH3), 4.34 (q, 4H, J = 6.9, CH2), 4.74(s, 4H, OCH2C=O), 5.66 (s, 4H, OCH2), 6.90 (d, 4H, J = 8.4 Hz, ArH), 6.95–7.09 (m, 6H, ArH and thiazol-5-H), 7.37 (d, 4H, J = 8.4 Hz, ArH), 7.65–7.70 (m, 8H, ArH), 7.74 (d, 4H, J = 9 Hz, ArH), 10.22 (s, 2H, NH), 11.01 (brs, 2H, NH); MS: m/z (%) 1292 (M+). Anal. Calcd. for C64H54Cl2N8O10S4: C, 59.39; H, 4.21; N, 8.66; S, 9.91. Found: C, 59.37; H, 4.23; N, 8.64; S, 9.88.

4.1.10. Synthesis of Isomeric Bis(thiazoles) Linked to Heteroaromatic Cores 10a,b, and 14a,b

To a solution of the appropriate bis(thiosemicarbazone derivatives) 9 or 13 (1 mmol) was added the α-bromoketone 6a,b (2 mmol) in ethanol (25 mL) containing TEA (0.2 mL). The reaction mixture was heated at reflux for 4 h. The obtained solid products upon cooling were filtered off and then recrystallized from ethanol/DMF to afford compounds 10a,b, and 14a,b.

4.1.11. 2,2′-(((((((Quinoxaline-2,3-diylbis(oxy))bis(4,1-phenylene))bis(ethan-1-yl-1-ylidene))bis(hydrazin-1-yl-2-ylidene))bis(thiazole-2,4-diyl))bis(4,1-phenylene))bis(oxy))bis(N-(p-tolyl)acetamide) (10a)

Brown powder, (77% yield); mp 270–271 °C; IR (KBr): 3315 (NH), 1693 (C=O), 1551 (C=N) cm–1; 1H NMR: δ 2.26 (s, 6H, CH3), 2.80 (s, 6H, CH3), 4.71 (s, 4H, OCH2C=O), 7.04 (d, 4H, J = 9 Hz, ArH), 7.12 (d, 4H, J = 7.8 Hz, ArH), 7.18 (s, 2H, thiazol-5-H), 7.47–7.82 (m, 20H, ArH), 9.97 (s, 2H, NH), 12.18 (brs, 2H, NH); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 20.5, 67.2, 101.8, 114.8, 119.8, 121.5, 122.9, 126.8, 129.2, 130.5, 132.7, 135.2, 135.8, 135.9, 141.1, 142.1, 150.6, 155.6, 157.3, 161.3, 166.3, 168.0; MS: m/z (%) 1070 (M+). Anal. Calcd. for C60H50N10O6S2: C, 67.27; H, 4.70; N, 13.08; S, 5.99. Found: C, 67.25; H, 4.71; N, 13.06; S, 5.95.

4.1.12. 2,2′-(((((((Quinoxaline-2,3-diylbis(oxy))bis(4,1-phenylene))bis(ethan-1-yl-1-ylidene))bis(hydrazin-1-yl-2-ylidene))bis(thiazole-2,4-diyl))bis(4,1-phenylene))bis(oxy))bis(N-(4-chlorophenyl)acetamide) (10b)

Brown powder, (79% yield); mp 273–275 °C; IR (KBr): 3280 (NH), 1683 (C=O), 1546 (C=N) cm–1; 1H NMR: δ 2.95 (s, 6H, CH3), 4.74 (s, 4H, OCH2C=O), 7.04 (d, 4H, J = 9 Hz, ArH), 7.18 (s, 2H, thiazol-5-H), 7.37–7.71 (m, 20H, ArH), 7.95 (d, 4H, J = 8.7 Hz, ArH), 10.21 (s, 2H, NH), 12.19 (brs, 2H, NH); 13C NMR (75 MHz, DMSO-d6) δ 17.5, 66.3, 105.6, 114.8, 119.8, 126.8, 127.0, 127.8, 128.3, 129.1, 129.4, 129.9, 132.7, 135.8, 141.2, 146.1, 150.2, 153.1, 157.3, 159.6, 166.3, 168.3, 172.3; MS: m/z (%) 1110 (M+). Anal. Calcd. for C58H44Cl2N10O6S2: C, 62.64; H, 3.99; N, 12.60; S, 5.77. Found: C, 62.61; H, 3.97; N, 12.61; S, 5.75.

4.1.13. Diethyl 3,4-Bis((4-(1-(2-(4-(4-(2-oxo-2-(p-tolylamino)ethoxy)phenyl)thiazol-2-yl)hydrazineylidene)ethyl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (14a)

Brown powder, (69% yield); mp 269–271 °C; IR (KBr): 3297 (NH), 1705 (C=O), 1681 (C=O), 1551 (C=N) cm–1; 1H NMR: δ 1.27 (t, 6H, J = 6.9, CH3), 2.25 (s, 6H, CH3), 2.80 (s, 6H, CH3), 4.33 (q, 4H, J = 6.9, CH2), 4.70 (s, 4H, OCH2C=O), 5.63 (s, 4H, OCH2), 6.91 (d, 4H, J = 8.7 Hz, ArH), 7.99–7.13 (m, 10H, ArH and thiazol-5-H), 7.46 (d, 4H, J = 8.1 Hz, ArH), 7.52 (d, 4H, J = 8.1 Hz, ArH), 7.74 (d, 4H, J = 8.7 Hz, ArH), 9.97 (s, 2H, NH), 11.92 (brs, 2H, NH); MS: m/z (%) 1252 (M+). Anal. Calcd. for C66H60N8O10S4: C, 63.24; H, 4.82; N, 8.94; S, 10.23. Found: C, 63.21; H, 4.80; N, 8.95; S, 10.22.

4.1.14. Diethyl 3,4-Bis((4-(1-(2-(4-(4-(2-((4-chlorophenyl)amino)-2-oxoethoxy)phenyl)thiazol-2-yl)hydrazineylidene)ethyl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (14b)

Brown powder, (73% yield); mp 261–263 °C; IR (KBr): 3295 (NH), 1711 (C=O), 1671 (C=O), 1550 (C=N) cm–1; 1H NMR: δ 1.28 (t, 6H, J = 6.9, CH3), 2.95 (s, 6H, CH3), 4.34 (q, 4H, J = 6.9, CH2), 4.73 (s, 4H, OCH2C=O), 5.64 (s, 4H, OCH2), 6.91 (d, 4H, J = 8.7 Hz, ArH), 7.00 (m, 4H, J = 8.7 Hz, ArH), 7.03 (s, 2H, thiazol-5-H), 7.37 (d, 4H, J = 8.7 Hz, ArH), 7.46 (d, 4H, J = 8.7 Hz, ArH), 7.68 (d, 4H, J = 8.7 Hz, ArH), 7.73 (d, 4H, J = 8.7 Hz, ArH), 10.20 (s, 2H, NH), 11.90 (brs, 2H, NH); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 18.1, 61.7, 65.1, 109.1, 112.7, 120.5, 120.6, 120.7, 122.2, 122.3, 122.4, 123.5, 125.0, 126.4, 130.8, 134.4, 138.1, 144.6, 149.1, 153.5, 156.5, 150.2, 162.5, 168.1, 173.2; MS: m/z (%) 1292 (M+). Anal. Calcd. for C64H54Cl2N8O10S4: C, 59.39; H, 4.21; N, 8.66; S, 9.91. Found: C, 59.36; H, 4.23; N, 8.64; S, 9.89.

4.2. Antibacterial Assay

The antibacterial activity of the synthesized compounds was tested by using the agar well diffusion technique. B. subtilis (DSM 1088) and S. aureus (ATCC 6538) were used as Gram-positive bacteria, whereas P. aeruginosa (ATCC 10145) and E. coli (ATCC 8739) were used as Gram-negative bacteria. Dimethyl sulfoxide (DMSO) was used as a carrier to create a solution for each synthesized compound (20 mg/mL). Bacterial centrifuged pellets from overnight culture with about 1 × 106 colony forming unit CFU per mL were cultivated on nutritional agar plates (yeast extract 0.5%, peptone 1%, NaCl 0.5%, agar 1.5%, distilled water 1 L, pH 7.2). Before use, the nutritional agar was autoclaved for at least 20 min at 121 °C. The nutrient agar plates were then allowed to cool to 45 °C. Following that, sterile metallic bores were used to create 6 mm wells in nutritional media. The activity was then evaluated by measuring the diameter of the inhibitory zone in millimeters. 20 L of the investigated chemicals (20 mg/mL) was poured into the plates’ prepared wells. As a negative control, a DMSO vehicle was added. As a positive control for S. aureus and E. coli, standard tobramycin80 (10 μg) was employed. For gram-positive and gram-negative bacteria, conventional clindamycin (2 g/disk) and ofloxacin81 (2 g/disk) were employed as positive controls, respectively. The plates were incubated at 37 °C for 24 h before the inhibitory zone diameter was measured in millimeters using a caliper.

4.3. Microdilution Assay

The microdilution technique was used to determine the MIC for compound 12b against B. subtilis (DSM 1088) established by CLSI.87 Briefly, (5 mg/mL) stock solution of compound 12b in DMSO was diluted in nutrient broth media to different concentrations (20, 10, 5, 2.5, 1.25, 0.625, and 0.3125 mg/mL). The DMSO final concentration was ≤2.5%, which does not affect the bacterial growth. The bacterial strain was transferred to fresh nutrient broth agar 1 day before the test. An overnight inoculum was prepared 12–16 h before the test and incubated overnight on a reciprocal shaker at 37 °C. 180 μL portion of the prepared bacterial suspension was then added to 20 μL of the tested compound which was present in every well of the microtitration plate. An eight-channel pipet was used to perform this procedure. The first well of the plate was taken as blank and contained 200 μL of liquid broth medium with 1% DMSO. The OD was read at a wavelength of 600 nm. Finally, the minimum concentration at which 100% of bacterial growth was inhibited (MIC) was determined.

4.4. Molecular Docking

The Molecular Operating Environment (MOE) version 2009.10 was used for the molecular docking simulation research. The program builder interface was used to draw the structures of the target compounds 8a, 8b, 12a, and 12b. Then, using the integrated MOPAC, they were subjected to local energy reduction. The compounds were then subjected to global energy reduction by systematic conformational search, with RMS distance and RMS gradient set to 0.1 Å and 0.01 kcal/mol, respectively. The protein database was used to derive the X-ray crystallographic structures of the bacterial dihydrofolate reductase and tyrosyl-tRNA synthetase proteins complexed with their cocrystallized ligands (PDB ID: 3FRA and 1JIJ, respectively). 5-[(2S)-2-Cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl]methylpyrimidine-2,4-diamine and 2-amino-3-(4-hydroxy-phenyl)-propionylamino-(1,3,4,5-tetrahydroxy-4-hydroxymethyl-piperidine-2-yl)-acetic acid were the cocrystallized ligands. The proteins were modified in the following ways: first, the proteins with their standard ligands were protonated. Following that, the target proteins’ undesirable water chains and cocrystallized ligands were eliminated. The MOE α site finder was then used to locate the active site of the chosen proteins, and fake atoms were created from the α spheres. Finally, the changed proteins were docked with the target molecules following self-docking with their cocrystallized ligands. Using BIOVIA Discovery Studio software V6.1.0.15350, the protein–ligand interactions were identified in the active domain and visualized in 2 and 3 dimensions.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c07125.

  • 1H NMR spectrum of compound 5a; 13C NMR spectrum of compound 5a; IR spectrum of compound 5a; mass spectrum of compound 5a; 1H NMR spectrum of compound 5b; 13C NMR spectrum of compound 5b; IR spectrum of compound 5b; mass spectrum of compound 5b; 1H NMR spectrum of compound 8a; 13C NMR spectrum of compound 8a; IR spectrum of compound 8a; mass spectrum of compound 8a; 1H NMR spectrum of compound 8b; 13C NMR spectrum of compound 8b; IR spectrum of compound 8b; mass spectrum of compound 8b; 1H NMR spectrum of compound 10a; 13C NMR spectrum of compound 10a; IR spectrum of compound 10a; mass spectrum of compound 10a; 1H NMR spectrum of compound 10b; 13C NMR spectrum of compound 10b; IR spectrum of compound 10b; mass spectrum of compound 10b; 1H NMR spectrum of compound 12a; 13C NMR spectrum of compound 12a; IR spectrum of compound 12a; mass spectrum of compound 12a; 1H NMR spectrum of compound 12b; IR spectrum of compound 12b; mass spectrum of compound 12b; 1H NMR spectrum of compound 14a; IR spectrum of compound 14a; mass spectrum of compound 14a; 1H NMR spectrum of compound 14b; 13C NMR spectrum of compound 14b; IR spectrum of compound 14b; and mass spectrum of compound 14b (PDF)

This work was supported and funded by the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU) (grant number IMSIU-RG23128).

The authors declare no competing financial interest.

Supplementary Material

ao3c07125_si_001.pdf (1.3MB, pdf)

References

  1. Hoffman P. S. Antibacterial Discovery: 21st Century Challenges. Antibiotics 2020, 9 (5), 213. 10.3390/antibiotics9050213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Atallah J.; Mansour M. K. Implications of Using Host Response-Based Molecular Diagnostics on the Management of Bacterial and Viral Infections: A Review. Front. Med. 2022, 9, 805107 10.3389/fmed.2022.805107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alizadeh S. R.; Hashemi S. M. Development and Therapeutic Potential of 2-Aminothiazole Derivatives in Anticancer Drug Discovery. Med. Chem. Res. 2021, 30, 771–806. 10.1007/s00044-020-02686-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Petrou A.; Fesatidou M.; Geronikaki A. Thiazole Ring—a Biologically Active Scaffold. Molecules 2021, 26 (11), 3166. 10.3390/molecules26113166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Turan-Zitouni G.; Altıntop M. D.; Kaplancıklı Z. A.; Özdemir A.; Demirci F.; Ilgın S.; Atlı Ö.; Göger G. Synthesis and Evaluation of Thiazole – Pyrimidine Derivatives as New Anticandidal and Cytotoxic Agents. Pharm. Chem. J. 2014, 48 (7), 452–455. 10.1007/s11094-014-1130-7. [DOI] [Google Scholar]
  6. Arshad M. F.; Alam A.; Alshammari A. A.; Alhazza M. B.; Alzimam I. M.; Alam M. A.; Mustafa G.; Ansari M. S.; Alotaibi A. M.; Alotaibi A. A.; Kumar S.; Asdaq S. M. B.; Imran M.; Deb P. K.; Venugopala K. N.; Jomah S. Thiazole: A Versatile Standalone Moiety Contributing to the Development of Various Drugs and Biologically Active Agents. Molecules 2022, 27 (13), 3994. 10.3390/molecules27133994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Osmaniye D.; Kayiş U.; Gül Ü. D.; Özkay Y.; Kaplancıklı Z. A. Synthesis, Biological Activity Evaluation and Molecular Docking Studies of Novel Thiazole Derivatives. Eur. J. Life Sci. 2023, 2 (1), 1–24. 10.55971/EJLS.1270394. [DOI] [Google Scholar]
  8. Altintop M. D.; Ozdemir A.; Asim Kaplancikli Z.; Turan-Zitouni G.; Iscan G.; Akalin Ciftci G. Synthesis and Biological Evaluation of Some Amide Derivatives Bearing Benzothiazole and Piperidine Moieties as Antimicrobial Agents. Lett. Drug Des. Discovery 2013, 10 (5), 453–461. 10.2174/1570180811310050013. [DOI] [Google Scholar]
  9. Kashyap A.; Adhikari N.; Das A.; Shakya A.; Ghosh S. K.; Singh U. P.; Bhat H. R. Review on Synthetic Chemistry and Antibacterial Importance of Thiazole Derivatives. Curr. Drug Discovery Technol. 2018, 15 (3), 214–228. 10.2174/1570163814666170911144036. [DOI] [PubMed] [Google Scholar]
  10. Scott K. A.; Njardarson J. T. Analysis of US FDA-Approved Drugs Containing Sulfur Atoms. Top. Curr. Chem. 2018, 376, 5 10.1007/s41061-018-0184-5. [DOI] [PubMed] [Google Scholar]
  11. Sharma P. C.; Bansal K. K.; Sharma A.; Sharma D.; Deep A. Thiazole-Containing Compounds as Therapeutic Targets for Cancer Therapy. Eur. J. Med. Chem. 2020, 188, 112016 10.1016/j.ejmech.2019.112016. [DOI] [PubMed] [Google Scholar]
  12. Pola S.Significance of Thiazole-Based Heterocycles for Bioactive Systems. In Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective; InTech: Rijeka, Croatia, 2016; Vol. 1, pp 13–62. [Google Scholar]
  13. Ali S. H.; Sayed A. R. Review of the Synthesis and Biological Activity of Thiazoles. Synth. Commun. 2021, 51, 670–700. 10.1080/00397911.2020.1854787. [DOI] [Google Scholar]
  14. Guo J.; Xie Z.; Ruan W.; Tang Q.; Qiao D.; Zhu W. Thiazole-Based Analogues as Potential Antibacterial Agents against Methicillin-Resistant Staphylococcus Aureus (MRSA) and Their SAR Elucidation. Eur. J. Med. Chem. 2023, 259, 115689 10.1016/j.ejmech.2023.115689. [DOI] [PubMed] [Google Scholar]
  15. Al-Ostoot F. H.; Zabiulla; Salah S.; Khanum S. A. Recent Investigations into Synthesis and Pharmacological Activities of Phenoxy Acetamide and Its Derivatives (Chalcone, Indole and Quinoline) as Possible Therapeutic Candidates. J. Iran. Chem. Soc. 2021, 18 (8), 1839–1875. 10.1007/s13738-021-02172-5. [DOI] [Google Scholar]
  16. Yele V.; Azam M. A.; Wadhwani A. D. Synthesis, Molecular Docking and Biological Evaluation of 2-Aryloxy-N-Phenylacetamide and N′-(2-Aryloxyoxyacetyl) Benzohydrazide Derivatives as Potential Antibacterial Agents. Chem. Biodivers. 2021, 18 (4), e2000907 10.1002/cbdv.202000907. [DOI] [PubMed] [Google Scholar]
  17. Tipparaju S. K.; Muench S. P.; Mui E. J.; Ruzheinikov S. N.; Lu J. Z.; Hutson S. L.; Kirisits M. J.; Prigge S. T.; Roberts C. W.; Henriquez F. L.; Kozikowski A. P.; Rice D. W.; McLeod R. L. Identification and Development of Novel Inhibitors of Toxoplasma Gondii Enoyl Reductase. J. Med. Chem. 2010, 53 (17), 6287–6300. 10.1021/jm9017724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sun A.; Prussia A.; Zhan W.; Murray E. E.; Doyle J.; Cheng L. T.; Yoon J. J.; Radchenko E. V.; Palyulin V. A.; Compans R. W.; Liotta D. C.; Plemper R. K.; Snyder J. P. Nonpeptide Inhibitors of Measles Virus Entry. J. Med. Chem. 2006, 49 (17), 5080–5092. 10.1021/jm0602559. [DOI] [PubMed] [Google Scholar]
  19. Ang W.; Lin Y. N.; Yang T.; Yang J. Z.; Pi W. Y.; Yang Y. H.; Luo Y. F.; Deng Y.; Wei Y. Q. Synthesis and Biological Evaluation of 2-(3-Fluoro-4-Nitro Phenoxy)-N-Phenylacetamide Derivatives as Novel Potential Affordable Antitubercular Agents. Molecules 2012, 17 (2), 2248–2258. 10.3390/molecules17022248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Guo J. L.; Liu Y. Y.; Pei Y. Z. Synthesis and Biological Evaluation of 3-(Piperidin-4-Yl)Isoxazolo[4,5-d]Pyrimidine Derivatives as Novel PI3Kδ Inhibitors. Chin. Chem. Lett. 2015, 26 (10), 1283–1288. 10.1016/j.cclet.2015.05.041. [DOI] [Google Scholar]
  21. Pal D.; Banerjee S.; Ghosh A. K. Dietary-Induced Cancer Prevention: An Expanding Research Arena of Emerging Diet Related to Healthcare System. J. Adv. Pharm. Technol. Res. 2012, 3 (1), 16–24. 10.4103/2231-4040.93561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pal D.; Mitra S. A Preliminary Study on the in Vitro Antioxidant Activity of the Stems of Opuntia Vulgaris. J. Adv. Pharm. Technol. Res. 2010, 1 (2), 268–272. [PMC free article] [PubMed] [Google Scholar]
  23. Nayak A. K.; Pal D.; Pany D. R.; Mohanty B. Evaluation of Spinacia Oleracea L. Leaves Mucilage as an Innovative Suspending Agent. J. Adv. Pharm. Technol. Res. 2010, 1 (3), 338–341. 10.4103/0110-5558.72430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Parhi A. K.; Zhang Y.; Saionz K. W.; Pradhan P.; Kaul M.; Trivedi K.; Pilch D. S.; Lavoie E. J. Antibacterial Activity of Quinoxalines, Quinazolines, and 1,5-Naphthyridines. Bioorg. Med. Chem. Lett. 2013, 23 (17), 4968–4974. 10.1016/j.bmcl.2013.06.048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Essassi E. M.; Ahoya C.; Bouhfid R.; Daouda B.; Hançali A.; Zouihri H.; Zerzouf A.; Aouad R. El. Synthesis and Antibacterial Activity of New Spiro[Thiadiazoline-Quinoxaline] Derivatives. Arkivoc 2011, 2011, 217–226. 10.3998/ark.5550190.0012.217. [DOI] [Google Scholar]
  26. Elhelby A. A.; Ayyad R. R.; Zayed M. F. Synthesis and Biological Evaluation of Some Novel Quinoxaline Derivatives as Anticonvulsant Agents. Drug Res. 2011, 61 (7), 379–381. 10.1055/s-0031-1296214. [DOI] [PubMed] [Google Scholar]
  27. Peraman R.; Kuppusamy R.; Killi S. K.; Reddy Y. P. New Conjugates of Quinoxaline as Potent Antitubercular and Antibacterial Agents. Int. J. Med. Chem. 2016, 2016, 6471352. 10.1155/2016/6471352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Chandra Shekhar A.; Shanthan Rao P.; Narsaiah B.; Allanki A. D.; Sijwali P. S. Emergence of Pyrido Quinoxalines as New Family of Antimalarial Agents. Eur. J. Med. Chem. 2014, 77, 280–287. 10.1016/j.ejmech.2014.03.010. [DOI] [PubMed] [Google Scholar]
  29. Wilhelmsson L. M.; Kingi N.; Bergman J. Interactions of Antiviral Indolo[2,3-b]Quinoxaline Derivatives with DNA. J. Med. Chem. 2008, 51 (24), 7744–7750. 10.1021/jm800787b. [DOI] [PubMed] [Google Scholar]
  30. Burguete A.; Pontiki E.; Hadjipavlou-Litina D.; Ancizu S.; Villar R.; Solano B.; Moreno E.; Torres E.; Pérez S.; Aldana I.; Monge A. Synthesis and Biological Evaluation of New Quinoxaline Derivatives as Antioxidant and Anti-Inflammatory Agents. Chem. Biol. Drug Des. 2011, 77 (4), 255–267. 10.1111/j.1747-0285.2011.01076.x. [DOI] [PubMed] [Google Scholar]
  31. Zhang M.; Dai Z. C.; Qian S. S.; Liu J. Y.; Xiao Y.; Lu A. M.; Zhu H. L.; Wang J. X.; Ye Y. H. Design, Synthesis, Antifungal, and Antioxidant Activities of (E)-6-((2-Phenylhydrazono)Methyl)Quinoxaline Derivatives. J. Agric. Food Chem. 2014, 62 (40), 9637–9643. 10.1021/jf504359p. [DOI] [PubMed] [Google Scholar]
  32. Lee S. H.; Kim N.; Kim S. J.; Song J.; Gong Y. D.; Kim S. Y. Anti-Cancer Effect of a Quinoxaline Derivative GK13 as a Transglutaminase 2 Inhibitor. J. Cancer Res. Clin. Oncol. 2013, 139 (8), 1279–1294. 10.1007/s00432-013-1433-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Suthar S. K.; Chundawat N. S.; Singh G. P.; Padrón J. M.; Jhala Y. K. Quinoxaline: A Comprehension of Current Pharmacological Advancement in Medicinal Chemistry. Eur. J. Med. Chem. Rep. 2022, 5, 100040 10.1016/j.ejmcr.2022.100040. [DOI] [Google Scholar]
  34. Ingle R.; Marathe R.; Magar D.; Patel H. M.; Surana S. J. Sulphonamido-Quinoxalines: Search for Anticancer Agent. Eur. J. Med. Chem. 2013, 65, 168–186. 10.1016/j.ejmech.2013.04.028. [DOI] [PubMed] [Google Scholar]
  35. Motakatla V. K. R.; Gokanapalli A.; Peddiahgari V. G. R. Cu–N-Heterocyclic Carbene-Catalysed Synthesis of 2-Aryl-3-(Arylethynyl)Quinoxalines from One-Pot Tandem Coupling of o-Phenylenediamines and Terminal Alkynes. Appl. Organomet. Chem. 2019, 33 (11), e5188 10.1002/aoc.5188. [DOI] [Google Scholar]
  36. Kheder N. A.; Mabkhot Y. N. Synthesis and Antimicrobial Studies of Some Novel Bis-[1,3,4]Thiadiazole and Bis-Thiazole Pendant to Thieno[2,3-b]Thiophene Moiety. Int. J. Mol. Sci. 2012, 13 (3), 3661–3670. 10.3390/ijms13033661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mabkhot Y. N.; Barakat A.; Yousuf S.; Choudhary M. I.; Frey W.; Ben Hadda T.; Mubarak M. S. Substituted Thieno[2,3-b]Thiophenes and Related Congeners: Synthesis, β-Glucuronidase Inhibition Activity, Crystal Structure, and POM Analyses. Bioorg. Med. Chem. 2014, 22 (23), 6715–6725. 10.1016/j.bmc.2014.08.014. [DOI] [PubMed] [Google Scholar]
  38. Litvinov V. P. The Latest Achievements in Thienothiophene Chemistry. Russ. Chem. Rev. 2005, 74 (3), 217–248. 10.1070/RC2005v074n03ABEH000889. [DOI] [Google Scholar]
  39. Heeney M.; Bailey C.; Genevicius K.; Shkunov M.; Sparrowe D.; Tierney S.; McCulloch I. Stable Polythiophene Semiconductors Incorporating Thieno[2,3-b]Thiophene. J. Am. Chem. Soc. 2005, 127 (4), 1078–1079. 10.1021/ja043112p. [DOI] [PubMed] [Google Scholar]
  40. Gather M. C.; Heeney M.; Zhang W.; Whitehead K. S.; Bradley D. D. C.; McCulloch I.; Campbell A. J. An Alignable Fluorene Thienothiophene Copolymer with Deep-Blue Electroluminescent Emission at 410 Nm. Chem. Commun. 2008, 9, 1079. 10.1039/b716510b. [DOI] [PubMed] [Google Scholar]
  41. Mcculloch I.; Heeney M.; Chabinyc M. L.; Delongchamp D.; Kline R. J.; Cölle M.; Duffy W.; Fischer D.; Gundlach D.; Hamadani B.; Hamilton R.; Richter L.; Salleo A.; Shkunov M.; Sparrowe D.; Tierney S.; Zhang W. Semiconducting Thienothiophene Copolymers: Design, Synthesis, Morphology, and Performance in Thin-Film Organic Transistors. Adv. Mater. 2009, 21 (10–11), 1091–1109. 10.1002/adma.200801650. [DOI] [Google Scholar]
  42. Melucci M.; Favaretto L.; Bettini C.; Gazzano M.; Camaioni N.; Maccagnani P.; Ostoja P.; Monari M.; Barbarella G. Liquid-Crystalline Rigid-Core Semiconductor Oligothiophenes: Influence of Molecular Structure on Phase Behaviour and Thin-Film Properties. Chem. – Eur. J. 2007, 13 (36), 10046–10054. 10.1002/chem.200701368. [DOI] [PubMed] [Google Scholar]
  43. Ahmed S. A.; Kamel M. S.; Aboelez M. O.; Ma X.; Al-Karmalawy A. A.; Mousa S. A. S.; Shokr E. K.; Abdel-Ghany H.; Belal A.; El Hamd M. A.; Al Shehri Z. S.; El Aleem Ali Ali El-Remaily M. A. Thieno[2,3- b]Thiophene Derivatives as Potential EGFRWTand EGFRT790MInhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies. ACS Omega 2022, 7 (49), 45535–45544. 10.1021/acsomega.2c06219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Jarak I.; Kralj M.; Piantanida I.; Šuman L.; Žinić M.; Pavelić K.; Karminski-Zamola G. Novel Cyano- and Amidino-Substituted Derivatives of Thieno[2,3-b]- and Thieno[3,2-b]Thiophene-2-Carboxanilides and Thieno[3′,2′:4,5]Thieno- and Thieno[2′,3′:4,5]Thieno [2,3-c]Quinolones: Synthesis, Photochemical Synthesis, DNA Binding, and Antitumor Evalu. Bioorg. Med. Chem. 2006, 14 (8), 2859–2868. 10.1016/j.bmc.2005.12.004. [DOI] [PubMed] [Google Scholar]
  45. Li Z.; Ono R. J.; Wu Z. Q.; Bielawski C. W. Synthesis and Self-Assembly of Poly(3-Hexylthiophene)-Block-Poly(Acrylic Acid). Chem. Commun. 2011, 47 (1), 197–199. 10.1039/C0CC02166K. [DOI] [PubMed] [Google Scholar]
  46. Hooshmand S. E.; Ghadari R.; Mohammadian R.; Shaabani A.; Khavasi H. R. Rhodanine-Furan Bis-Heterocyclic Frameworks Synthesis via Green One-Pot Sequential Six-Component Reactions: A Synthetic and Computational Study. ChemistrySelect 2019, 4 (40), 11893–11898. 10.1002/slct.201903361. [DOI] [Google Scholar]
  47. Al-Jumaili M. H. A.; Hamad A. A.; Hashem H. E.; Hussein A. D.; Muhaidi M. J.; Ahmed M. A.; Siddique F.; Bakr E. A. Comprehensive Review on the Bis–heterocyclic Compounds and Their Anticancer Efficacy. J. Mol. Struct. 2023, 1271, 133970 10.1016/j.molstruc.2022.133970. [DOI] [Google Scholar]
  48. Kerru N.; Singh P.; Koorbanally N.; Raj R.; Kumar V. Recent Advances (2015–2016) in Anticancer Hybrids. Eur. J. Med. Chem. 2017, 142, 179–212. 10.1016/j.ejmech.2017.07.033. [DOI] [PubMed] [Google Scholar]
  49. Alkhzem A. H.; Woodman T. J.; Blagbrough I. S. Design and Synthesis of Hybrid Compounds as Novel Drugs and Medicines. RSC Adv. 2022, 12 (30), 19470–19484. 10.1039/D2RA03281C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ibrahim N. S.; Sroor F. M.; Mahrous K. F.; Elaleem J. A. A.; Abdelhamid I. A. Cytotoxic Effect of New (E)-2-Cyano-N-(Tetrahydrobenzo[b]Thiophen-2-Yl)Acrylamide Derivatives: Down-Regulation of RBL2 and STAT2 and Triggering of DNA Damage in Breast Carcinoma. ChemistrySelect 2023, 8 (33), e202301754 10.1002/SLCT.202301754. [DOI] [Google Scholar]
  51. Geweely N. S.; Hassaneen H. M.; Ali R. A.; Soliman M. M.; Abdelhamid I. A. New Inhibitory Effect by Green Synthesized Chalcone Derivatives on the Fungal Deterioration of Archaeological Egyptian Mummy, Egypt. Polycycl. Aromat. Compd. 2023, 10.1080/10406638.2023.2231595. [DOI] [Google Scholar]
  52. Sroor F. M.; Abdelmoniem A. M.; Abdelhamid I. A. Facile Synthesis, Structural Activity Relationship, Molecular Modeling and In Vitro Biological Evaluation of New Urea Derivatives with Incorporated Isoxazole and Thiazole Moieties as Anticancer Agents. ChemistrySelect 2019, 4 (34), 10113–10121. 10.1002/slct.201901415. [DOI] [Google Scholar]
  53. Ghozlan S. A. S.; Mohamed M. H.; Abdelmoniem A. M.; Abdelhamid I. A. Synthesis of Pyridazines and Fused Pyridazines via [3 + 3] Atom Combination Using Chitosan as a Green Catalyst. Arkivoc 2009, 10, 302–311. 10.3998/ark.5550190.0010.a27. [DOI] [Google Scholar]
  54. El-gabry Y. A.; Salem M. E.; Ibrahim N. S.; Elwahy A. H. M.; Abdelhamid I. A.; Diab H. M. Novel Diphenyl Ether-Heterocycles Hybrids : Synthesis via Hantzsch and Biginelli Reactions, Molecular Docking Simulation, and Antimicrobial Activities. J. Mol. Struct. 2024, 1296 (P2), 136857 10.1016/j.molstruc.2023.136857. [DOI] [Google Scholar]
  55. Abdelmoniem A. M.; Abdelwahab R. E.; Elwahy A. H. M.; Abdelhamid I. A. Regioselective Synthesis of Fused Pyrimidines and Quinazolines Linked to Phenoxy-N-Arylacetamide Moieties as Novel Hybrid Molecules via Biginelli-like Reaction. J. Heterocycl. Chem. 2023, 60, 1699. 10.1002/jhet.4709. [DOI] [Google Scholar]
  56. Hammad H. F.; Darweesh A. F.; Abdelaziz M. A.; Elwahy A. H. M.; Abdelhamid I. A. Synthesis of Novel Dihydropyridine, Fused Dihydropyridines, Hexahydrobenzo[4,5]Imidazo[2,1-b]Quinazolines, and Fused-Pyrans Linked to Piprazine Core via Benzoyloxyacetyl Likages as New Hybrid Molecules Utilizing Michael, and Hantzsch Reaction. Synth. Commun. 2023, 53 (16), 1305–1318. 10.1080/00397911.2023.2220441. [DOI] [Google Scholar]
  57. Abdelmoniem A. M.; Hassaneen H. M. E.; Abdelhamid I. A. An Efficient One-Pot Synthesis of Novel Spiro Cyclic 2-Oxindole Derivatives of Pyrimido[4,5-b]Quinoline, Pyrido[2,3-d:6,5-D′]Dipyrimidine and Indeno[2′,1′:5,6]Pyrido [2,3-d]Pyrimidine in Water. J. Heterocycl. Chem. 2016, 53 (6), 2084–2090. 10.1002/jhet.2480. [DOI] [Google Scholar]
  58. Abdelhamid I. A.; Darwish E. S.; Nasra M. A.; Abdel-Gallil F. M.; Fleita D. H. Synthesis and Chemical Reactivity of New Azaenamines Incorporated the 4,5,6,7-Tetrahydrobenzo[b]Thiophene Moiety: 3 + 3 Atom Combination. Synthesis 2010, 2010, 1107–1112. 10.1055/s-0029-1219235. [DOI] [Google Scholar]
  59. Al-Awadi N. A.; Abdelkhalik M. M.; Abdelhamid I. A.; Elnagdi M. H. Pyrolytic Methods in Organic Synthesis: Novel Routes for the Synthesis of 3-Oxoalkanenitriles, 2-Acyl Anilines, and 2-Aroyl Anilines. Synlett 2007, 2007, 2979–2982. 10.1055/S-2007-992355. [DOI] [Google Scholar]
  60. Mohamed M. F.; Mohamed M. S.; Fathi M. M.; Shouman S. A.; Abdelhamid I. A. Chalcones Incorporated Pyrazole Ring Inhibit Proliferation, Cell Cycle Progression, Angiogenesis and Induce Apoptosis of MCF7 Cell Line. Anticancer Agents Med. Chem. 2014, 14 (9), 1282–1292. 10.2174/187152061409141010114547. [DOI] [PubMed] [Google Scholar]
  61. Ghozlan S. A. S.; Abdelhamid I. A. A.; Elnagdi M. H. H. Functionally Substituted Arylhydrazones as Building Blocks in Heterocyclic Synthesis: Routes to Pyridazines and Pyridazinoquinazolines. Arkivoc 2006, 2006, 147–157. 10.3998/ark.5550190.0007.d15. [DOI] [Google Scholar]
  62. Al-Awadi N. A.; Abdelhamid I. A.; Abdelhamid I.; Al-Etaibi A. M.; Al-Etaibi A.; Elnagdi M. H. Gas-Phase Pyrolysis in Organic Synthesis: Rapid Green Synthesis of 4-Quinolinones. Synlett 2007, 2007, 2205–2208. 10.1055/s-2007-985573. [DOI] [Google Scholar]
  63. Diab H. M.; Elsayed B.; Darweesh A. F.; Abdelhamid I. A.; Elwahy A. H. M. Synthesis of Novel Bis(Sulfanediyl)Bis(Tetrahydropyrimido[4,5-b]Quinoline-4,6-Diones) Linked to Butenyl and Butynyl Spacers via Thioether Linkages. Polycycl. Aromat. Compd. 2023, 43 (5), 4084–4102. 10.1080/10406638.2022.2083192. [DOI] [Google Scholar]
  64. Sroor F. M.; Aboelenin M. M.; Mahrous K. F.; Mahmoud K.; Elwahy A. H. M.; Abdelhamid I. A. Novel 2-Cyanoacrylamido-4,5,6,7-Tetrahydrobenzo[b]Thiophene Derivatives as Potent Anticancer Agents. Arch. Pharm. 2020, 353 (10), e2000069 10.1002/ardp.202000069. [DOI] [PubMed] [Google Scholar]
  65. Darweesh A. F.; Abd El-Fatah N. A.; Abdelhamid I. A.; Elwahy A. H. M.; Salem M. E. Investigation of the Reactivity of (1H-Benzo[d]Imidazol-2-Yl)Acetonitrile and (Benzo[d]Thiazol-2-Yl)Acetonitrile as Precursors for Novel Bis(Benzo[4,5]Imidazo[1,2-a]Pyridines) and Bis(Benzo[4,5]Thiazolo[3,2-a]Pyridines). Synth. Commun. 2020, 50 (16), 2531–2544. 10.1080/00397911.2020.1784436. [DOI] [Google Scholar]
  66. Salem M. E.; Hosny M.; Darweesh A. F.; Elwahy A. H. M. Synthesis of Novel Bis- and Poly(Aryldiazenylthiazoles). Synth. Commun. 2019, 49 (18), 2319–2329. 10.1080/00397911.2019.1620283. [DOI] [Google Scholar]
  67. Hosny M.; Salem M. E.; Darweesh A. F.; Elwahy A. H. M. Synthesis of Novel Bis(Thiazolylchromen-2-One) Derivatives Linked to Alkyl Spacer via Phenoxy Group. J. Heterocycl. Chem. 2018, 55 (10), 2342–2348. 10.1002/jhet.3296. [DOI] [Google Scholar]
  68. Salem M. E.; Fares I. M. Z.; Ghozlan S. A. S.; Abdel-Aziz M. M.; Abdelhamid I. A.; Elwahy A. H. M. Facile Synthesis and Antimicrobial Activity of Bis(Fused 4H-Pyrans) Incorporating Piperazine as Novel Hybrid Molecules: Michael’s Addition Approach. J. Heterocycl. Chem. 2022, 59 (11), 1907–1926. 10.1002/jhet.4525. [DOI] [Google Scholar]
  69. Diab H. M.; Salem M. E.; Abdelhamid I. A.; Elwahy A. H. M. Synthesis of Novel Star-Shaped Molecules Based on a 1,3,5-Triazine Core Linked to Different Heterocyclic Systems as Novel Hybrid Molecules. RSC Adv. 2020, 10 (72), 44066–44078. 10.1039/D0RA09025E. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Muathen H. A.; Aloweiny N. A. M.; Elwahy A. H. M. Synthesis of Novel Amide-Crownophanes and Schiff Base-Crownophanes Based on p-Phenylene, 2,6-Naphthalene, and 9,10-Anthracene. J. Heterocycl. Chem 2009, 46, 656–663. 10.1002/jhet.129. [DOI] [Google Scholar]
  71. A Ibrahim Y.; H M Elwahy A.; A Abbas A. New Synthesis of Macrocyclic Crown-Formazans from Pyruvic Acid Derivatives. Tetrahedron 1994, 50 (39), 11489–11498. 10.1016/S0040-4020(01)89286-3. [DOI] [Google Scholar]
  72. Ibrahim Y. A.; Abbas A. A.; Elwahy A. H. M. New Trends in the Chemistry of Condensed Heteromacrocycles Part B: Macrocyclic Formazans. J. Heterocycl. Chem. 2004, 41 (2), 135–149. 10.1002/jhet.5570410202. [DOI] [Google Scholar]
  73. Barsoum B. N.; Khella S. K.; Elwaby A. H. M.; Abbas A. A.; Ibrahim Y. A. Evaluation of Some New 14- and 15-Crown-Formazans as Carriers in Cesium Ion Selective Electrodes. Talanta 1998, 47 (5), 1215–1222. 10.1016/S0039-9140(98)00204-5. [DOI] [PubMed] [Google Scholar]
  74. Sayed O. M.; Mekky A. E. M.; Farag A. M.; Elwahy A. H. M. 3,4-Bis(Bromomethyl)Thieno[2,3-b]Thiophene: Versatile Precursors for Novel Bis(Triazolothiadiazines), Bis(Quinoxalines), Bis(Dihydrooxadiazoles), and Bis(Dihydrothiadiazoles). J. Heterocycl. Chem. 2016, 53, 1113–1120. 10.1002/jhet.2373. [DOI] [Google Scholar]
  75. Elwahy A.; Shaaban M. Synthesis of Pyrido- and Pyrimido-Fused Heterocycles by Multi-Component Reactions (Part 3). Curr. Org. Synth. 2014, 11 (6), 835–873. 10.2174/157017941106141023114039. [DOI] [Google Scholar]
  76. Fathi E. M.; Sroor F. M.; Mahrous K. F.; Mohamed M. F.; Mahmoud K.; Emara M.; Elwahy A. H. M.; Abdelhamid I. A. Design, Synthesis, In Silico and In Vitro Anticancer Activity of Novel Bis-Furanyl-Chalcone Derivatives Linked through Alkyl Spacers. ChemistrySelect 2021, 6 (24), 6202–6211. 10.1002/slct.202100884. [DOI] [Google Scholar]
  77. Elwahy A. H. M.; Ginidi A. R. S.; Shaaban M. R.; Farag A. M.; Salem M. E. Synthesis of Novel Bis-Thiazoles, Bis-Thienopyridines, and Bis-Triazolothiadiazines Linked to Diphenyl Ether Core as Novel Hybrid Molecules. Synth. Commun. 2023, 53, 426–441. 10.1080/00397911.2023.2179405. [DOI] [Google Scholar]
  78. Salem M. E.; Qenawy M. S.; Farag A. M.; Elwahy A. H. M. Synthesis of Novel Scaffolds Based on Bis-Thiazole or Bis-Triazolothiadiazine Linked to Quinoxaline as New Hybrid Molecules. Synth. Commun. 2023, 53 (2), 103–118. 10.1080/00397911.2022.2153338. [DOI] [Google Scholar]
  79. Sayed O. M.; Mekky A. E. M.; Farag A. M.; Elwahy A. H. M. 3,4-Dimethyl-2,5-Functionalized Thieno[2,3-b[Thiophenes: Versatile Precursors for Novel Bis-Thiazoles. J. Sulfur Chem. 2015, 36 (2), 124–134. 10.1080/17415993.2014.975131. [DOI] [Google Scholar]
  80. Sroor F. M.; Othman A. M.; Tantawy M. A.; Mahrous K. F.; El-Naggar M. E. Synthesis, Antimicrobial, Anti-Cancer and in Silico Studies of New Urea Derivatives. Bioorg. Chem. 2021, 112, 104953 10.1016/j.bioorg.2021.104953. [DOI] [PubMed] [Google Scholar]
  81. Umar A.; Patas M.; Adamu M.; Musa U.; Jauro H.; Maigana Z.; Puma H. Occurrence and Antibiogram of Bacteria Isolated from Some Sachet Drinking Water Brands Sold in Gombe Metropolis, Gombe State, Nigeria. Microbes Infect. Dis. 2022, 3 (3), 720–725. 10.21608/mid.2021.98676.1199. [DOI] [Google Scholar]
  82. He J.; Qiao W.; An Q.; Yang T.; Luo Y. Dihydrofolate Reductase Inhibitors for Use as Antimicrobial Agents. Eur. J. Med. Chem. 2020, 195, 112268. 10.1016/j.ejmech.2020.112268. [DOI] [PubMed] [Google Scholar]
  83. Raju A.; Kulkarni S.; Ray M. K.; Rajan M. G. R.; Degani M. S. E84G Mutation in Dihydrofolate Reductase from Drug Resistant Strains of Mycobacterium Tuberculosis (Mumbai, India) Leads to Increased Interaction with Trimethoprim. Int. J. Mycobacteriol. 2015, 4 (2), 97–103. 10.1016/j.ijmyco.2015.02.001. [DOI] [PubMed] [Google Scholar]
  84. Sun J.; Lv P. C.; Zhu H. L. Tyrosyl-TRNA Synthetase Inhibitors: A Patent Review. Expert Opin. Ther. Pat. 2017, 27, 557–564. 10.1080/13543776.2017.1273350. [DOI] [PubMed] [Google Scholar]
  85. Guo M.; Schimmel P. Essential Nontranslational Functions of TRNA Synthetases. Nat. Chem. Biol. 2013, 9 (3), 145–153. 10.1038/nchembio.1158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Abdullah A. H.Synthesis of Bis(Functional) Compounds, Ph.D. Thesis, Faculty of Science, Department of Chemistry, Cairo University, 2023. [Google Scholar]
  87. Barry A. L.; Craig W. A.; Nadler H.; Reller L. B.; Sanders C. C.; Swenson J. M.. M26-A: Methods for Determining Bactericidal Activity of Antimicrobial Agents; Approved Guideline; Clinical and Laboratory Standards Institute, 1999; pp 1–29.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao3c07125_si_001.pdf (1.3MB, pdf)

Articles from ACS Omega are provided here courtesy of American Chemical Society

RESOURCES