Thiadiazole Ring Research Articles

Compounds Designs of CK2α Inhibitors Derived from Virtual Screening Hit Compounds by Computational Chemistry with Crystallography.

Protein kinase CK2 type α (CK2α) inhibitors are expected to be a new anticancer drug and a treatment for nephritis. Virtual screening for CK2α inhibitors has been conducted and active compounds with various scaffolds have been obtained. Research on compound optimization is currently in progress for some of them with the aim of improving their activity. This process involves the combination of various computational chemistry methods and crystal analyses. In this review, case studies of structure-based compound designs that have efficiently improved the activity of screening hit compounds, including compounds with a thiadiazole ring and a purine scaffold, are introduced.

Exploring molecular fragments for fraction unbound in human plasma of chemicals: a fragment-based cheminformatics approach

ABSTRACT Fraction unbound in plasma (f u,p) of drugs is an significant factor for drug delivery and other biological incidences related to the pharmacokinetic behaviours of drugs. Exploration of different molecular fragments for f u,p of different small molecules/agents can facilitate in identification of suitable candidates in the preliminary stage of drug discovery. Different researchers have implemented strategies to build several prediction models for f u,p of different drugs. However, these studies did not focus on the identification of responsible molecular fragments to determine the fraction unbound in plasma. In the current work, we tried to focus on the development of robust classification-based QSAR models and evaluated these models with multiple statistical metrics to identify essential molecular fragments/structural attributes for fractions unbound in plasma. The study unequivocally suggests various N-containing aromatic rings and aliphatic groups have positive influences and sulphur-containing thiadiazole rings have negative influences for the f u,p values. The molecular fragments may help for the assessment of the f u,p values of different small molecules/drugs in a speedy way in comparison to experiment-based in vivo and in vitro studies.

A reactive flame retardant based on thiadiazole and phosphaphenanthrene for improving the flame retardant and smoke inhibition properties of epoxy resins

AbstractIt is difficult to effectively manage the emission of harmful smoke from flame‐retardant modified epoxy resins (EP). In order to solve this difficulty, a highly efficient flame‐resistant PAD containing phosphorus, nitrogen, and sulfur was synthesized using a simply one‐pot method employing 9,10‐dihydro‐9‐oxa‐10‐phosphaphenanthrene‐10‐oxide (DOPO), 2‐amino‐5‐mercapto‐1,3,4‐thiadiazole (AMT), and terephthalaldehyde for not only enhancing its flame retardant properties but also effectively suppressing the emission of fumes. Results have confirmed that the incorporation of 5 wt% flame retardant into the EP successfully passed the UL‐94 V‐0 rating, besides 24.2% reduction in the peak of smoke produce rate (PSPR), with outstanding fire‐resistant properties and effectively reduce smoke emissions. In addition, incorporating 7.5% of PAD into EP increased its flexural strength and modulus, from 78.4 and 2917.5 to 86.6 and 3162.9 MPa, respectively. Due to the abundance of reactive groups including sulfhydryl and secondary amine in PAD, as well as the nitrogen atoms presented in the thiadiazole and benzene rings of the phosphaphenanthrene structure, which could create hydrogen bonds with the matrix and participated in π‐π interactions, therefore, the mechanical properties of flame retardant epoxy resin (FREP) were greatly enhanced.

Synthesis of tetrazole hybridized with thiazole, thiophene or thiadiazole derivatives, molecular modelling and antimicrobial activity

BackgroundTetrazole-based derivatives and their electronic structures have displayed interesting antimicrobial activity. MethodsThe tetrazole-based hybrids linked with thiazole, thiophene and thiadiazole ring systems have been synthesized through various chemical reactions. The computational method DFT/B3LYP has been utilized to calculate their electronic properties. The antimicrobial effectiveness was investigated against representative bacterial and fungal strains. Additionally, the synthesized derivatives binding interaction was stimulated by docking program against PDB ID: 4URO as a model of the ATP binding domain of S. aureus DNA Gyrase subunit B. ResultsThe structures of the synthesized tetrazole-based derivatives were confirmed by IR, NMR, and Mass spectroscopic data. The DFT/B3LYP method showed that the thiadiazole derivatives 9a–c had lower ΔEH-L than the thiophenes 7a–c and thiazoles 5a–c. The hybrids 5b, 5c, and 7b exhibited proper antibacterial activity against Gram’s +ve bacterial strains (S. aureus and S. pneumonia), while 9a displayed potent activity towards Gram’s -ve bacterial strains (S. typhimurium and E. coli). Meanwhile, derivatives 5a-b, 7a, 7c, and 9c showed good effectiveness towards fungal strain (C. albicans). ConclusionThe study provides valuable tetrazole core-linked heterocyclic rings and opens the door to further research on their electrical characteristics and applications. Tetrazoles and thiazoles have antibacterial properties in pharmacological frameworks, making these hybrids potential lead molecules for drug development. The conclusion summarizes the data and suggests that the synthesized chemicals' interaction with a particular protein domain suggests focused biological activity.

Synthesis and Biological Evaluation of Novel Thiadiazole Derivatives as Antiplatelet Agents.

A novel series of thiadiazole compounds was synthesized through the reaction of thiosemicarbazone intermediates with 2, 3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The antiplatelet activity of the synthesized compounds was evaluated using an aggregation test with adenosine diphosphate (ADP) and arachidonic acid (AA) as platelet aggregation inducers. Among the synthesized analogs, compound 3b exhibited the most potent inhibition of platelet aggregation induced by ADP (half maximal inhibitory concentration [IC50] = 39 ± 11 µM). Molecular docking studies of 3b revealed hydrogen bonds between the nitrogen of the thiadiazole ring and Lys280. The tolyl ring exhibited hydrophobic interactions with Tyr105, similar to the antagonist co-crystallized with P2Y12 (PDB ID: 4NTJ). These compounds have the potential to serve as lead molecules for designing P2Y12 inhibitors.

Tailoring helical ends of π-extended [6]heterohelicenes to control optical, and electrochemical features.

The inherent helical chirality and improved π-stacking capabilities endow helicenes with fascinating photophysical characteristics when decorated with lateral π-extensions. Here, we report the synthesis and physicochemical characterization of expanded hetero[6]helicenes fused with thiadiazole and selenadiazole rings at the helical ends. Comparing these heterohelicenes revealed the impact of the heteroatom-embedded aromatic rings on the excited state and redox features. A small structural variation of the terminal rings from thiadiazole to selenadiazole caused a striking change in the heterohelical nanographenes.

Synthesis of naproxen thiadiazole urea hybrids and determination of their anti-melanoma, anti-migration, tyrosinase inhibitory activity, and molecular docking studies

Novel sixteen naproxen urea compounds were synthesized bearing the thiadiazole ring. Their inhibitory activities against tyrosinase were investigated. 3o was discovered to be the most potent inhibitor of tyrosinase, with an IC50 value of 35.0 µM. The kinetic parameters were used to determine the type of enzyme inhibition. The results showed that 3o was an uncompetitive inhibitor with the Ki value of 62.2 µM. Additionally, the cytotoxic effects of the synthesized compounds on melanoma (B16F10), mouse embryonic (3T3) and the healthy 3T3 cell lines were also investigated. According to the cytotoxicity results, 3e (IC50= 2.17 µM) showed the highest cytotoxicity on the B16F10 cells. Furthermore, the effects of selected compounds on the migration rate of melanoma cells were investigated. In addition, molecular modeling studies were also performed and the results showed the possible interactions between the uncompetitive inhibitor 3o with the Tyrosinase-L-Tyrosine enzyme substrate complex.

Unveiling the adsorption and inhibition mechanism of thiadiazole derivatives for mild steel corrosion in hydrochloric acid based on experimental approaches and first-principles calculations

In this work, two eco-friendly thiadiazole derivatives, 5-amino-1,2,3-thiadiazole (AT) and N-phenyl-N-1,2,3-thiadiazol-5-yluree (thidiazuron, TDZ), were employed to alleviate the corrosion of mild steel in hydrochloric acid medium. Electrochemical tests show that compared to AT, TDZ exhibits a much better inhibitive effect with an inhibition efficiency of 98.95% at 0.6 mM. The introduced side chain with phenyl ring in TDZ molecule endues it with more adsorption sites, which facilitates the strong absorption of TDZ by the extra bonding of O atom and phenyl ring with steel surface. The DFT-based first-principles calculations indicate that AT and TDZ could adsorb on the steel surface through the thiadiazole ring, O atom and phenyl ring by forming Fe–S, Fe–N, Fe–O, and Fe–C bonds. The parallel adsorptions of AT and TDZ are more stable with more negative adsorption energy than their perpendicular adsorptions. Furthermore, the non-covalent interaction between AT/TDZ and H2O solvent molecules deteriorates their adsorptions on steel surface.

Synthesis of flurbiprofen thiadiazole urea derivatives and assessment of biological activities and molecular docking studies.

Totally 15 novel flurbiprofen urea derivatives were synthesized bearing the thiadiazole ring. Their inhibition effects on tyrosinase were determined. 3c was found to be the strongest inhibitor with the IC50 value of 68.0 μM against tyrosinase. The enzyme inhibition types of the synthesized compounds were determined by examining the kinetic parameters. The inhibition type of 3c was determined as uncompetitive and the Ki value was calculated as 36.3 μM. Moreover, their cytotoxic effects on hepatocellular carcinoma (HepG2), colorectal carcinoma (HT-29), and melanoma (B16F10) cell lines were evaluated. According to the cytotoxicity results, 3l (IC50 = 14.11 μM) showed the highest cytotoxicity on the HT-29 cells, while 3o (IC50 = 4.22 μM) exhibited the strongest cytotoxic effect on HepG2 cell lines. Also, 3j (IC50 = 7.55 μM strongly affected B16F10. The effects of synthesized compounds on the healthy cell line were evaluated on the CCD-986Sk cell line. Molecular modelling studies have indicated the potential binding interactions of the uncompetitive inhibitor 3c with the enzyme-substrate complex.

Synthesis and Anticancer Activities of Pyrazole-Thiadiazole-Based EGFR Inhibitors.

Lung cancer is one of the most common cancer types of cancer with the highest mortality rates. However, while epidermal growth factor receptor (EGFR) is an important parameter for lung cancer, EGFR inhibitors also show great promise in the treatment of the disease. Therefore, a series of new EGFR inhibitor candidates containing thiadiazole and pyrazole rings have been developed. The activities of the synthesized compounds were elucidated by in vitro MTT, (which is chemically 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), cytotoxicity assay, analysis of mitochondrial membrane potential (MMP) by flow cytometry, and EGFR inhibition experiments. Molecular docking and molecular dynamics simulations were performed as in silico studies. Compounds 6d, 6g, and 6j showed inhibitor activity against the A549 cell line with IC50 = 5.176 ± 0.164; 1.537 ± 0.097; and 8.493 ± 0.667 μM values, respectively. As a result of MMP by flow cytometry, compound 6g showed 80.93% mitochondrial membrane potential. According to the results of the obtained EGFR inhibitory assay, compound 6g shows inhibitory activity on the EGFR enzyme with a value of IC50 = 0.024 ± 0.002 μM.

Therapeutic charisma of imidazo [2,1-b] [1,3,4]-thiadiazoleanalogues: a patent review.

Imidazothiadiazole was discovered around the 1950s era, containing an imidazole ring fused to a thiadiazole ring. Imidazothiadiazole exhibit versatile pharmacological properties including anticonvulsant, cardiotonic, anti-inflammatory, diuretic, antifungal, antibacterial and anticancer. Despite of the being discovered in 1950s, the imidazothiadiazole derivatives are unable to being processed to clinical trials because of lack of bioavailability, efficacy and cytotoxicity. The recent patent literature focused on structural modification of imidazothiadiazole core to overcome these problems. This review limelight a disease-centric perspective on patented imidazothiadiazole from 2015-2023 and to understand their mechanism of action in related diseases. The relevant granted patent applications were located using patent databases, Google Patents, USPTO, EPO, WIPO, Espacenet and Lens.

Efficient synthesis of novel 2-deoxy-C-nucleosides containing oxa and thiadiazole derivatives and their biological activity

Five membered oxa- and thiadiazole derivatives have shown significant biological activity due to their unique bioisosteric properties. Herein, we describe an efficient synthetic approach leading to several novel C-nucleosides containing an oxadiazole or thiadiazole ring system. This work provides for the first-time ability to assemble β-C-nucleosides in a facile manner offering an ideal framework for the possible development of new antiviral and antitumor drugs. All new C-nucleosides were tested for their activity against TBEV and SARS-CoV-2. Two of the synthesized compounds exerted mild anti-SARS-CoV-2 activity, as evidenced by the decrease in viral titers by <1 log10 PFU/ml compared with controls. Mechanism for the formation of 5-substituted 1,3,4-thiadiazole ring is proposed and a structure-activity relationship established with these C-nucleosides.

Crystal structure of 5-(β-d-gluco-pyran-osyl-thio)-N-(4-methyl-phen-yl)-1,3,4-thia-diazol-2-amine.

In the structure of the title compound, C15H19N3O5S2, the bond lengths at the linking sulfur atom are significantly different [1.7473 (17) and 1.811 (2) Å], and the angle at the exocyclic nitro-gen atom is wide at 128.45 (18)°. The inter-planar angle between the tolyl and thia-diazole rings is 9.2 (1)°. The complex hydrogen-bonding pattern, involving five donors and five acceptors, can be broken down into a one-dimensional ribbon parallel to the b axis, involving hydrogen bonds of the sugar residues only, and a two-dimensional layer structure parallel to the ab plane, based on the N-H⋯O and O-H⋯N hydrogen bonds.

Multi-method evaluation of a 2-(1,3,4-thiadiazole-2-yl)pyrrolidine corrosion inhibitor for mild steel in HCl: combining gravimetric, electrochemical, and DFT approaches

The corrosion inhibition properties of 2-(1,3,4-thiadiazole-2-yl)pyrrolidine (2-TP) on mild steel in a 1 M HCl solution were investigated using weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy (EIS) and open circuit potential (OCP) measurements. In addition, DFT calculations were performed on 2-TP. The polarization curves revealed that 2-TP is a mixed-type inhibitor. The results indicate that 2-TP is an effective inhibitor for mild steel corrosion in a 1.0 M HCl solution, with an inhibition efficiency of 94.6% at 0.5 mM 2-TP. The study also examined the impact of temperature, revealing that the inhibition efficiency increases with an increasing concentration of 2-TP and decreases with a rise in temperature. The adsorption of the inhibitor on the mild steel surface followed the Langmuir adsorption isotherm, and the free energy value indicated that the adsorption of 2-TP is a spontaneous process that involves both physical and chemical adsorption mechanisms. The DFT calculations showed that the adsorption of 2-TP on the mild steel surface is mainly through the interaction of the lone pair of electrons on the nitrogen atom of the thiadiazole ring with the metal surface. The results obtained from the weight loss, potentiodynamic polarization, EIS and OCP measurements were in good agreement with each other and confirmed the effectiveness of 2-TP as a corrosion inhibitor for mild steel in 1.0 M HCl solution. Overall, the study demonstrates the potential use of 2-TP as a corrosion inhibitor in acid environments.

Synthesis, Characterization and Antibacterial study of some 1, 3, 4- thiadiazole ring appended azo derivatives

A series of 1,3,4-thiadiazole ring appended azo derivatives were synthesized in good yields via diazo coupling reaction between 5-(4-substituted)-1,3,4-thiadiazole-2-amine and some active methyline compounds such as dimedone and acetylacetone. All the synthesized compounds were characterized by FT-IR and 1HNMR spectroscopic methods. Further, all synthesized compounds were screened for the antibacterial activity against gram negative bacteria (Escherichia coli, Pseudomonas aruginosa, Shigella boydii) and gram-positive bacteria (Staphylococcus aureus, Bacillus megaterium). The thiadiazole ring appended azo derivative containing a chloro group showed potent activity against Shigella boydii (67.85%) and Staphylococcus aureus (78.57%) and the compound having a nitro group in its structure exhibited maximum zone of inhibition against Staphylococcus aureus (89.28%) and Shigella boydii (82.14%).

Fusing thiadiazol and terephthalate: A concept to promote the electrochemical performance of conjugated dicarboxylates.

Organic electrode materials based on conjugated dicarboxylate moieties are particularly attractive to develop metal-ion organic batteries. Exhibiting good stability properties in liquid electrolytes, such organic electrode materials can reversibility store alkali metal ions (Li, Na or K) at low working potential. Although many molecular designs have been investigated in the last decade, conjugated dicarboxylates are impeded by low Coulombic efficiencies, especially at the first cycle, and sluggish kinetics in most cases. Herein, we report on a new strategy in the design of conjugated carboxylates by fusing a thiadiazole heterocycle to the terephthalate core. We investigate for the first time the synthesis and electrochemical performance of dilithium-2,1,3-benzothiadiazole-4,7-dicarboxylate (Li2-DCBTZ) as positive electrode material. Next to being a new structural design, the presence of the thiadiazole ring enables (i) a better conjugation of p-n electrons leading to a benefit in terms of rate capability, and (ii) a better stabilizing coordination network for Li ions through both oxygen and nitrogen atoms. In addition, the reduced state in Li4-DCBTZ is stabilized due to a maintained aromaticity in the heteroaromatic core in comparison to the parent terephthalate. Theoretical calculations on the Li-ion storage mechanism and bonding character support the experimental work.

Synthesis, Anticancer, Antimicrobial and Antioxidant Potential of Novel 4-(Substituted phenyl-1,3,4-oxadiazol/thiadiazol-2-yl)-4-(4-substituted phenyl) Azetidin-2-One Derivatives.

By exploiting the ample biological potential of 1,3,4-oxadiazole/thiadiazole ring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. Various substituted azetidin-2-one derivatives have been identified as immunostimulating and antimicrobial, as well as their antioxidant activity. 2-amino 1,3,4 oxadiazole/thiadiazole conjugates were synthesized by mixing semi/thio carbazides and sodium acetate with water and stirring well, followed by adding aldehydes in methanol at room temperature. Acetate (glacial) was used as the catalyst to produce Schiff's bases (intermediates) by treating substituted aldehydes with 2-amino 1,3,4 oxadiazole/thiadiazole(s). Using the mixture of triethylamine (dropwise) and chloroacetylchloride with vigorous stirring, 4-substitutedphenyl-1,3,4-oxadiazol/Thiadiazol-2-yl)-4-(4-substitutedphenyl) azetidin-2-one derivatives were prepared. The newly synthesized conjugates were evaluated for their anticancer potential using MCF-7 cell lines. Amoxicillin and fluconazole were used as reference drugs to determine their antimicrobial activity. Synthesized derivatives were evaluated for their antioxidant properties using 2-diphenyl-1-picrylhydrazyl (DPPH). In vitro cytotoxicity screening (MTTS assay) revealed that derivatives AZ-5, 9, 10, 14 and 19 demonstrated high efficacy with the percentage of inhibition at different concentration ranges (0.1 μM, 0.5 μM, 1 μM, 2 μM) of 89% to 94% μM as compared to doxorubicin as standard drug. The antimicrobial study indicated that compounds AZ-10, 19, and AZ-20 were found to have significant antimicrobial potential with MIC ranges of 3.34 µM to 3.71 µM in comparison to reference drugs having 4.29 µM to 5.10 µM. Based on antioxidant screening, most of the synthetic derivatives showed greater stability and effectiveness than the standard drug. According to the antioxidant screening, compounds AZ-5 and AZ-15 (IC50 = 45.02 μg/mL and 42.88 μg/mL, respectively) showed the greatest potency, as compared to ascorbic acid (IC50 = 78.63 μg/mL). Structure-activity relationship (SAR) studies of synthesized novel derivatives revealed that para-substituted halogen and nitro derivatives have remarkable potential against MCF-7 cancer cell lines and different microbial strains. Current evidence indicates that the synthesized derivatives may be promising candidates for use in the prevention and treatment of these infections. These synthesized compounds require further mechanism-based research to understand how they interact with the cells.

New expanded porphyrinoids: Synthesis, structure and properties of hemihexaphyrazines and their reduced metal containing derivatives

Hemihexaphyrazines can be considered as hexamembered porphyrinoids of the ABABAB type, where thiadiazole rings (A) and pyrrole-containing subunits (B) joined via aza bridges to form a macrocyclic system with an expanded coordination cavity capable of holding at once three atoms of transition metals that are formed a triangular cluster. It was established for the first time that unsubstituted hemihexaphyrazine and its metal complexes can be reduced to form crystalline salts. These salts were characterized by UV-Vis-NIR and IR spectroscopy, MS, and X-Ray diffraction data. The magnetic properties of these compounds were studied for the first time using EPR and SQUID techniques within the [Formula: see text] K temperature range. It was shown that the three-electron reduction of starting [Formula: see text] yields [Formula: see text] and [Formula: see text] crystalline salts. An unusual doublet-quartet transition was found for the [Formula: see text] dianions. Salt [Formula: see text] also shows an unusually strong low energy NIR absorption, which was observed at 1000–2200 nm with maxima located at 1283 and 1980 nm. A phenomenon consisting of equalization of bond lengths among exocyclic nitrogen atoms ([Formula: see text] and neighboring atoms C(pyrrole) and C(thiadiazole) was observed under reduction conditions.

Diverse Biological Activities of 1,3,4-Thiadiazole Scaffold

The chemistry of 1,3,4-thiadiazole is one of the most interesting scaffolds for synthesizing new drug molecules due to their numerous pharmacological activities. Several modifications in the thiadiazole ring have been made, proving it to be more potent and highly effective with a less toxic scaffold for various biological activities. There are several marketed drugs containing 1,3,4-thiadiazole ring in their structure. In this review article, we have tried to compile the newly synthesized 1,3,4-thiadiazole derivatives possessing important pharmaceutical significance since 2014.

Novel S-Mercaptotriazolebenzothiazole-Based Derivatives as Antimicrobial Agents: Design, Synthesis, and In Vitro Evaluation

Background: The search for novel antimicrobial agents effective against the emerging resistant pathogenic microorganisms to the currently used drugs is a substantial need. Herein, a novel series of compounds bearing a benzothiazolotriazole scaffold was synthesized and evaluated as potential antimicrobial agents against a panel of gram +ve, gram -ve bacteria, and fungi species. Methods: The new compounds were synthesized via hybridization between the benzothiazolotriazole scaffold and thiadiazole ring or various substituted aromatic moieties using the tethering technique in drug discovery. Results: The in vitro results revealed that these compounds have significant antifungal activity rather than antibacterial potential due to their high similarity with tricyclazole. Compound 7b bearing bromo-phenyl moiety was the most potent derivative with an MIC value of 8 μg/mL against Candida albicans and Penicillium chrysogenum. Conclusion: Collectively, benzothiazolotriazole-based derivatives are good antifungal leads and should be further actively pursued to expand treatment options for systemic and topical fungal infections.