Substituted Thiazole Derivatives Research Articles

Molecular modelling and antimicrobial activity of newly synthesized benzothiazolo[3,2-a]pyrimidine clubbed thiazole derivatives

A series of benzothiazolopyrimidine-thiazole conjugates 7, 8, and 9 were produced through the reactions of 8-acetylbenzothiazolopyrimidine-thiosemicarbazone compound 6 with chloroacetone, (un)substituted phenacyl chlorides, and ethyl chloroacetate, respectively. Based on DFT study, the synthesized conjugates had a twisted shape, except for the parent benzothiazolopyrimidine 5 and its thiosemicarbazone compound 6, which were flat. The study of FMO's also showed that the substituted thiazole derivatives 7 and 8a-c have equivalent configurations of HOMO and LUMO, as well as exhibiting the least FMO's gap (ΔEH-L). The antimicrobic activeness of the constructed derivatives has been assessed against the two Gram's types of bacteria and fungi using the broth microdilution method. The benzothiazolopyrimidine-thiazole conjugate 8c exhibited the strongest inhibition towards Gram-negative E. coli (MIC <29 μg/mL), while a valuable performance was observed towards S. typhimurium (MIC <132 μg/mL). Also, it displayed broad-spectrum activity with the least MIC versus C. albicans fungi (<207 μg/mL). In contrast, the conjugate 8b demonstrated selective efficacy against Gram + ve S. aureus and B. subtilis bacteria (MIC <40 and < 47 μg/mL, respectively). Besides, molecular docking of these benzothiazolopyrimidine derivatives with the PDB: 2XCT protein carried out to discover their binding types, RMSD, binding scores, and interactions pocket for each derivative, including a drug reference. Furthermore, their physicochemical-pharmacokinetic profile has estimated via the SwissADME prediction. The data indicated that derivative 5 demonstrated constructive pharmacokinetics (M. Wt. 269.28), lipophilicity (Log Po/w = 1.45), and TPSA = 103.47, which foretold high (GI) absorption and good bioavailability = 0.55 without interrupting Lipinski's rules.

Thiadiazole and Thiazole Derivatives as Potential Antimicrobial Agents.

This review summarizes data on heterocyclic systems with thiadiazole and thiazole fragments in molecules as promising antimicrobial agents. Thiadiazole and thiazole backbones are the most favored and well-known heterocycles, a common and essential feature of various drugs. These scaffolds occupy a central position and are the main structural components of numerous drugs with a wide spectrum of action. These include antimicrobial, antituberculous, anti-inflammatory, analgesic, antiepileptic, antiviral, and anticancer agents. The research is based on bibliosemantic and analytical methods using bibliographic and abstract databases, as well as databases of chemical compounds. This review reports on thiadiazole and thiazole derivatives, which have important pharmacological properties. We are reviewing the structural modifications of various thiadiazole and thiazole derivatives, more specifically, the antimicrobial activity reported over the last years, as we have taken this as our main research area. 80 compounds were illustrated, and various derivatives containing hydrazone bridged thiazole and pyrrole rings, 2-pyridine and 4-pyridine substituted thiazole derivatives, compounds containing di-, tri- and tetrathiazole moieties, spiro-substituted 4- thiazolidinone-imidazoline-pyridines were analyzed. Derivatives of 5-heteroarylidene-2,4- thiazolidinediones, fluoroquinolone-thiadiazole hybrids, and others. 1,3,4-thiadiazoles and thiazoles are valuable resource for researchers engaged in rational drug design and development in this area.

A simple route for the synthesis of substituted thiazole derivatives by multicomponent reaction between arylglyoxals, acetylacetone or ethyl acetoacetate, and thiosemicarbazones

A simple route for the synthesis of substituted thiazole derivatives by multicomponent reaction between arylglyoxals, acetylacetone or ethyl acetoacetate, and thiosemicarbazones

Synthesis and Structure Determination of Substituted Thiazole Derivatives as EGFR/BRAFV600E Dual Inhibitors Endowed with Antiproliferative Activity.

2,3,4-trisubstituted thiazoles 3a-i, having a methyl group in position four, were synthesized by the reaction of 1,4-disubstituted thiosemicarbazides with chloroacetone in ethyl acetate/Et3N at room temperature or in ethanol under reflux. The structures of new compounds were determined using NMR spectroscopy, mass spectrometry, and elemental analyses. Moreover, the structure of compound 3a was unambiguously confirmed with X-ray analysis. The cell viability assay of 3a-i at 50 µM was greater than 87%, and none of the tested substances were cytotoxic. Compounds 3a-i demonstrated good antiproliferative activity, with GI50 values ranging from 37 to 86 nM against the four tested human cancer cell lines, compared to the reference erlotinib, which had a GI50 value of 33 nM. The most potent derivatives were found to be compounds 3a, 3c, 3d, and 3f, with GI50 values ranging from 37 nM to 54 nM. The EGFR-TK and BRAFV600E inhibitory assays' results matched the antiproliferative assay's results, with the most potent derivatives, as antiproliferative agents, also being the most potent EGFR and BRAFV600E inhibitors. The docking computations were employed to investigate the docking modes and scores of compounds 3a, 3c, 3d, and 3f toward BRAFV600E and EGFR. Docking computations demonstrated the good affinity of compound 3f against BRAFV600E and EGFR, with values of -8.7 and -8.5 kcal/mol, respectively.

Substituted Thiazole Derivatives Provide Corrective Anti-tumour and Anti-oxidant Activities against Ehrlich Ascites Carcinoma.

Novel and effective treatments are urgently needed for cancer, which is still the leading cause of death in the world. Biological characteristics linked to thiazole derivatives span a wide range. Thiazole derivatives are used in the creation of medications for therapy as well. The aim of current study is to evaluate the anticancer and antioxidant properties of the newly synthesized thiazole derivatives, compounds 1 and 2, on Ehrlich ascites carcinoma (EAC) cells in female mice. Our findings indicated that thiazole derivatives, compounds 1 and 2 have anticancer activity by elevating the p53 expression and cytochrome c levels in groups treated with compounds 1 and 2 compared to the positive control group. Furthermore, thiazole derivatives compounds 1 and 2 showed a potent antioxidant effect by increasing enzymatic antioxidants, catalase (CAT) activity, and non-enzymatic antioxidants, GSH, and lowering Malondialdehyde (MDA) in hepatic and renal tissues of treated groups. Additionally, the target compounds were capable of providing corrective effects against EAC-induced biochemical and histopathological changes without harmful side effects. CONCLUSION: The target studied thiazol derivatives compounds were capable of providing corrective effects against EAC-induced without harmful side effects.

Design, In-Silico Studies, Synthesis, Characterization, and Anticonvulsant Activities of Novel Thiazolidin-4-One Substituted Thiazole Derivatives

A series of novel thiazolidine-4-one substituted thiazoles were prepared using multi-step synthesis and screened for their antiepileptic potency. The chemical nature of the prepared derivatives was confirmed using FT-IR, elemental analyses, Mass spectroscopy, and 1H-NMR. Molecular properties and antiepileptic potency of the novel thiazoles were predicted using in-silico models such as molinspiration online tool and molecular docking, respectively. In-vivo antiepileptic potency of the entire title compounds was determined using MES and scPTZ method. Additionally, the rotorod test was employed to determine the neurotoxicity of the synthesized derivatives. Entire title analogs displayed -varying degrees of antiepileptic and neurotoxicity potency. The pharmacological potency of tested compounds was compared with their chemical structures. 2-(4-Nitrophenyl)-3-(4-((4-phenylthiazol-2-ylimino)methyl)phenyl) thiazolidin-4-one (PTT6) was found to be the very active derivative of this series among thirteen tested derivatives. Thus, this analog may act as a lead molecule to find potent and safer antiepileptic drugs.

A Facile Synthesis of New Substituted Thiazol-2-amine Derivatives as Potent Antimicrobial Agent

A facile synthesis of a new thiazol-2-amine derivative as antimicrobial agent and condensation with substituted thiourea compounds to afford the corresponding substituted thiazole derivatives in excellent yields. All the reactions were completed within less reaction time at reflux temperature. According to the result obtained, the compounds 3b, 3d, 3e, 3f, 3g, 3i, 3l, and 3m were found the leader antimicrobial activity with the highest MIC values. The synthesized compound can be considered to develop new antimicrobial drug candidates. Amongst these, many compounds show better antibacterial and antifungal activity. The compounds 3b, 3d, 3e, 3l, and 3m exhibited significant antibacterial activity against B. subtilis, S. aureus, and E. coli. The compounds 3f, 3g, 3i show significant antifungal against fungal strains i.e., C. albicans, A. flavus and A. niger.

ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES OF NOVEL HETEROCYCLIC SUBSTITUTED THIAZOLE DERIVATIVES

A set of new heterocyclic substituted thiazole derivatives were synthesized as powerful analgesic and antiinflammatory agents with minimal ulcer index. Spectroscopic and elemental analyses were employed to confirm the chemical structures of the prepared compounds. Molecular properties, ADME properties, drug-likeness scores, and toxicities of title compounds were predicted using insilico studies. In addition, title compounds were docked against two proteins namely, 3KK6 and 3LN1 using AutoDock 4.2. Tail-flick method and carrageenan-induced foot paw oedema methods were used to screen in vitro analgesic and anti-inflammatory activities of title compounds, respectively. Moreover, the ulcerogenicity of potent compounds of the series was also determined. Most of the novel heterocyclic substituted thiazoles produced, mild-to-good analgesic and anti-inflammatory activity with a low-toreasonable ulcer index. Out of thirteen tested derivatives the most potent compound was found to be 1-(4- chlorophenyl)-4-(2-(4-(4-methoxyphenyl)thiazol-2-yl)hydrazono)-3-methyl-1H-pyrazol-5(4H)-one.

Coupled large amplitude motions: The effects of two methyl internal rotations and 14N quadrupole coupling in 4,5-dimethylthiazole investigated by microwave spectroscopy

The molecular jet Fourier-transform microwave spectrum of 4,5-dimethylthiazole has been recorded between 2.0 and 26.5 GHz, revealing torsional splittings arising from two inequivalent methyl internal rotations with relatively low hindering barriers and nitrogen quadrupole hyperfine structures. Two global fits with 1009 hyperfine components of 97 rotational transitions involving 315 torsional lines were performed using the program XIAM and BELGI-Cs-2Tops-hyperfine, an extended version of the BELGI-Cs-2Tops code which includes the effect of the 14N quadrupole coupling, giving a root-mean-square deviation of 399.8 kHz and 4.2 kHz, respectively. Compared to the monomethyl substituted thiazole derivatives, the barriers to internal rotation are drastically lower. This is also in contrast to chemical intuition which suggests high barriers due to steric hindrance. Because of the strong interaction between the methyl groups, strong top-top couplings in both the potential energy and kinetic parts of the Hamiltonian were observed.

Synthesis of a Series of Substituted Thiazole Derivatives: New COX‐2 Enzyme Inhibitors for Colon Cancer and Inflammation Treatment

AbstractA variety of thiazoles motif linked with diethyl 2‐amino‐5‐hydroxy‐1H‐pyrrol‐3‐ylphosphonate were synthesized in 70 to 84% yields. Before the synthesis, the prospective biological activity spectrum was predicted for the suggested structures (and others) with PASS program, http://www.pharmaexpert.ru. Based on a preliminary assay of antiproliferative activity, selected six new phosphonates were evaluated against the most common human colorectal adenocarcinoma cell lines: HT‐29, Caco‐2, SW‐1417, SW‐480, SW‐948, HCT‐116, and HCT‐15. Three phosphonates showed GI50 values within the range 2.18‐7.77 μM compared with the standard reference, Adriamycin ranged 3.27‐8.64 μM. Based on the knowledge about the role of the cyclooxygenase‐2 into the cell growth and the inflammation mechanism, a hypothesis of molecular modeling study that included the fitting of all synthesized compounds into 2D and 3D‐pharmacophore was undertaken. Discovery Studio 2.5 software was applied and the docking into human COX‐2 enzyme revealed good results that are consistent with the pharmacological assessments. The experimental biological evaluation activities of new phosphonates showed high approximation with their molecular modeling results as well as the early prospecting prediction of biological activity.

Discovery of Thiazole Based Bis Heterocyclic System for Anti- Inflammatory Potential.

We have developed a new series of 36 substituted thiazole derivatives prepared via reaction of substituted benzothiazole-2-amine with substituted phenacyl bromide. This study was aimed to develop and successfully evaluate anti-inflammatory activity of substituted thiazole derivatives. A new series of 36 substituted thiazole derivatives was synthesized and derivatives were characterized by analytical and spectrometric methods like IR, MS, and 1H NMR. The molecular docking was performed for all the synthesized thiazole derivatives to assess their binding affinities to COX-2 isozyme. The best compounds from docking study were subjected for their anti-inflammatory activity by using rat hind paw edema method. Results from carrageenan-induced hind paw edema showed that compounds 3h, 5a, 5e, 9d, and 9h possess significant anti-inflammatory activity. The result from vascular permeability indicating inhibition of vascular permeability with compounds 3h and 9h is significant and results from cotton pellet granuloma formation models show greater degree of inhibition with compounds 3h and 5a to contribute to their significant anti-inflammatory activity. This study provides successful development of novel thiazole derivatives. Their binding affinities to COX-2 enzyme were also confirmed, indicating that developed molecules are comparable to diclofenac and hence could be promising anti-inflammatory agents.

Substituted (E)-2-(2-benzylidenehydrazinyl)-4-methylthiazole-5-carboxylates as dual inhibitors of 15-lipoxygenase & carbonic anhydrase II: synthesis, biochemical evaluation and docking studies

15-Lipoxygenase (15-LOX) plays a major role in many inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), asthma and chronic bronchitis. Over-expression of 15-LOX is related with some specific carcinomas including pancreatic, gastric and brain tumor. Similarly among different isozymes of carbonic anhydrase (CA), CA II is expressed in pancreatic, gastric carcinomas as well as in brain tumors. Therefore, novel potent inhibitors of both 15-LOX and CA II are required to explore the role of these enzymes further and to enable the drug discovery efforts. For this purpose, a series of benzyledinyl-hydrazinyl substituted thiazole derivatives were designed, synthesized and characterized by FTIR, 1H, &13C NMR spectroscopy. The derivatives were then evaluated for their potential to inhibit 15-LOX and bovine carbonic anhydrase II (bCA II). Most of these compounds showed excellent inhibitory potential for 15-LOX with an IC50 of 0.12 ± 0.002 to 0.69 ± 0.5 μM and showed moderate inhibition potency for bCA II with compound 5h (IC50 = 1.26 ± 0.24 μM) being the most active. The most potent compound 5a that emerged as a dual inhibitor of both enzymes, exhibiting 24 times greater selectivity for 15-LOX over bCA II. Compound 5a exhibited dual potent inhibitory activity against both 15-LOX and bCA II enzymes having IC50 values of 0.12 ± 0.002 and 2.93 ± 0.22 μM, respectively. Molecular docking studies of potent as well as dual inhibitors were also carried out to provide an insight into the binding site interactions.

Synthesis, Cytotoxic Evaluation, Docking and QSAR Study of N-(4-Oxo- 2-(4-((5-Aryl-1,3,4-Thiadiazol-2-yl)Amino)Phenyl)Thiazolidin-3-yl) Benzamides as Antitubulin Agents.

In the present study an efficient strategy for the synthesis of thiazole and thiadiazole derivatives was developed and clubbed together both of the substituted nucleus to form the analogues of combretastatin A-4 (tubulin polymerization inhibitors.). Synthesis was started by the reaction of substituted benzoic acid with thionyl chloride followed by the reaction with hydrazine, p-chloro benzaldehyde and thioglycolic acid to form substituted thiazole derivatives. On the other side hydrazides were reacted with ammonium thiocyanate and strong acid to form substituted thiadiazole compounds. Finally thiazole and thiadiazole compounds were clubbed with the help of dioxan and triethylamine. All novel derivatives (TH01-TH40) were screened for their cytotoxicity activity using MTT assay against three cancer cell lines viz. A-549 (lung carcinoma), HT-29 (colon carcinoma), HeLa (cervix carcinoma). Compounds TH08 exhibited highest activity, due to the presence of trimethoxy substitution on phenyl ring. In QSAR study these results were correlated with physicochemical parameters and the correlation of XlogP, kaapa2, Quadrupole1 with cytotoxic activity on A-549 (lung carcinoma) was found highest (r2: 0.941; F: 99.103; Se: 0.0006). In docking study binding of active molecule (TH08) was found very well with α, β tubulin (PDB: 1SA0) protein.

Cadmium Chloride (CdCl2): An Efficient Catalyst for the Synthesis of Substituted Thiazoles

A variety of α-bromoketones undergoes smooth condensation with thiourea compounds to afford the Corresponding substituted thiazole derivatives in very good to excellent yields. The condensation reactions were carried out in presence of cadmium chloride in acetonitrile at room temperature.

In vitro Reactivation of Chlorpyrifos-inhibited Rat Brain Acetylcholinesterase from 2-Quinolone Substituted Thiazole derivatives

Organophosphate (OP) compounds exert inhibition of acetylcholinesterase (AChE) by irreversibly binding to catalytic site of an enzyme. Despite continued efforts to discover improved reactivators, there has been little success towards innovation of AChE reactivators. In the present investigation, new series of 2-quinolone fused thiazole derivatives 3a-3f and 4a-4f were evaluated for their in vitro reactivation efficacy against chlorpyrifos inhibited AChE using 2-PAM as standard. Even though the non oxime derivatives were not as effective as pralidoxime (2-PAM), but exhibited considerable AChE reactivation. The compounds, 3b, 3c, 3f, and 4f, showed promising reactivation against chlorpyrifos inhibited AChE.

Docking, synthesis, and pharmacological investigation of novel substituted thiazole derivatives as non-carboxylic, anti-inflammatory, and analgesic agents

A series of substituted thiazole derivatives (6–16) were synthesized to obtain new compounds with potential anti-inflammatory and analgesic activities. At equimolar oral doses, compounds 3-(piperidin-1-yl-methyl)-1, 3, 4-oxadiazol-2-thione (14), 5-amino-4-ethyl ester pyrazole (15), and 5-amino-3-phenylpyrazole derivatives (16) displayed anti-inflammatory and analgesic activities significant to those of diclofenac sodium in the carrageenan-induced paw edema test in rat and acetic acid-induced writhing test in mice,-respectively. The most active members of the series (9, 11, 14, 15, and 16) were selected for ulcerogenic potential study. These compounds exhibited quite less ulcerogenic index in the range of 0.44 to 0.62 whereas diclofenac sodium showed 4.67. The docking study results also indicated that the compound 6, 7, 8, 11, and 14 exhibited the docking score ranging from −3.951 to −4.691.

ChemInform Abstract: Catalysis by Zeolite Leading to the Construction of Thiazole Ring: An Improved Synthesis of 4‐Alkynyl Substituted Thiazoles.

Abstract Zeolite H-beta facilitated the reaction of α-chloro acetyl chloride with 1,2-bis-trimethyl silyl acetylene to give 1-chloro-4-(trimethylsilyl)but-3-yn-2-one which on treatment with thioacetamide afforded 2-methyl-4-[(trimethylsilyl)ethynyl]thiazole. l -Proline on the other hand facilitated the coupling reaction of 2-methyl-4-[(trimethylsilyl)ethynyl]thiazole with (hetero)aryl halides (modified Sonogashira reaction) under Pd-Cu catalysis in the presence of aqueous K 2 CO 3 affording an improved method for the synthesis of corresponding 4-alkynyl substituted thiazole derivatives.

Arylazolyl(azinyl)thioacetanilide. Part 9: Synthesis and biological investigation of thiazolylthioacetamides derivatives as a novel class of potential antiviral agents

In continuation of our endeavor to develop new, potent, selective and less toxic antiviral agents, a novel series of 2-(2-amino/chloro-4-(2,4-dibromophenyl) thiazol-5-ylthio)acetamide derivatives was synthesized via an expeditious route and evaluated for their anti-HIV activities against wild-type virus and clinically relevant mutant strains, and for their anti-influenza virus activities against influenza A (H1N1 and H3N2) and influenza B in cellular assays. The selected active compounds were also assayed for their enzymic inhibitory activities. The results showed that some 2-chloro substituted thiazolylthioacetamide derivatives possessed potent activity against wild type HIV-1 and several key mutant strains (E138K, K103N, L100I) of HIV-1 in MT-4 cells with EC(50) values in micromolar range. Two 2-amino substituted thiazole derivatives 8a7 and 8a8 displayed significant potency against influenza A/H1N1 in MDCK cells with EC(50) values much lower than that of oseltamivir carboxylate, ribavirin, amantadine and rimantadine. Though the mechanism of actions is still unclear, these novel thiazolylthioacetamides might serve as original leads for further pharmacological investigations as potential therapeutic agents against HIV-1 or influenza virus.

Catalysis by zeolite leading to the construction of thiazole ring: an improved synthesis of 4-alkynyl substituted thiazoles

Zeolite H-beta facilitated the reaction of α-chloro acetyl chloride with 1,2-bis-trimethyl silyl acetylene to give 1-chloro-4-(trimethylsilyl)but-3-yn-2-one which on treatment with thioacetamide afforded 2-methyl-4-[(trimethylsilyl)ethynyl]thiazole. l-Proline on the other hand facilitated the coupling reaction of 2-methyl-4-[(trimethylsilyl)ethynyl]thiazole with (hetero)aryl halides (modified Sonogashira reaction) under Pd-Cu catalysis in the presence of aqueous K2CO3 affording an improved method for the synthesis of corresponding 4-alkynyl substituted thiazole derivatives.

ChemInform Abstract: Synthesis, Characterization, in vitro and Molecular Docking Studies of New 2,5‐Dichloro Thienyl Substituted Thiazole Derivatives for Antimicrobial Properties.

AbstractThe new compounds (IV), containing a dichlorothienyl‐substituted thiazole ring system, which resemble a known antifungal agent are screened for antifungal and antibacterial activities.