Thiazole Compound Research Articles

The discovery of indazapyroxamet: a novel 3-pyridinyl insecticide targeting piercing/sucking insectsa.

In recent years, the registrations for a number of commercial insecticides utilized for piercing/sucking insects have been cancelled or restricted. To meet this growing need for new hemipteran controlling agrochemicals, we discovered a 2-(pyridin-3-yl)-thiazole compound, with limited insecticidal activity against cotton/melon aphid (Aphis gossypii). The 2-(pyridin-3-yl)-thiazole moiety offered us a basis to pursue the bicyclic 2-(pyridin-3-yl)-2H-indazole carboxamides. Evaluation of such 2-(pyridin-3-yl)-2H-indazole carboxamides revealed that even analogs containing only simple alkyl amides attached at the 4 or 5 positions possess promising insecticidal activity. Extensive optimization of this novel class of 2-(pyridin-3-yl)-2H-indazole carboxamides led to identifying indazapyroxamet for commercial development. © 2024 Society of Chemical Industry.

Investigation of the effects of thiazole compounds on thioredoxin reductase 1 (TrxR1), glutathione S-transferase (GST), and glutathione reductase (GR) targeted human brain glioblastoma cancer (U-87 MG).

Cancer is a fatal disease that kills thousands of people worldwide. Despite the information produced by research on cancer treatment, applications in cancer treatment are limited. Therefore, scientists' efforts to develop more effective treatment approaches continue. In the study, we aimed to determine the anticancer potential of amino thiazole compounds on human glioblastoma (U-87 MG) and human dermal fibroblast (HDFa) cells and their inhibition effects on enzymes that cause multidrug resistance in cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide cell viability test was performed to understand the cytotoxic properties of thiazole derivatives. The cellular death mechanisms behind thiazole application were investigated using flow cytometry analysis. According to cell viability analysis, thiazole derivatives exhibited a greater effect on U-87 MG than the HDFa cell line in terms of cytotoxicity. Flow cytometry showed higher apoptotic cell death in U-87 MG cells than in the HDFa cell line. It can be concluded that thiazole compounds exert anticancer effects on U-87 MG and HDFa as well as show apoptotic properties. Their effects on thioredoxin reductase 1 (TrxR1), glutathione S-transferase (GST), and glutathione reductase (GR) activities, which are important in the development of chemotherapeutic methods, were also examined. From the results obtained, it was determined that the 2-amino-4-(p-tolyl)thiazole (T7) compound significantly suppressed both TrxR1 and GST activities, and the 2-amino-6-methylbenzothiazole (T8) compound significantly suppressed both TrxR1 and GST activities. Compound T7 was determined to be a selective inhibitor for TrxR1 and GST targeting, and compound T8 was determined to be a selective inhibitor for TrxR1 and GR targeting glioblastoma treatment.

Synthesis, characterization and anticancer evaluation of novel 4-hydrazinothiazole analogues.

Single-step synthesis of novel 4-hydrazinothiazole derivatives 6a-e was achieved under mild conditions via the sequential four components method using isothiocyanate, aminoguanidine, carbonyl adduct, and α-haloketone derivatives. Deprotection of these hydrazinothiazoles was influenced by acylation, providing a novel group of diacylated molecular structures with a broader scope for the design of thiazolyl-containing drugs 7a and 7b. FTIR, 1 H/13 C NMR, LC-MS spectroscopy, and CHN elemental analyses have been used to study the compounds' chemical structures. Using an MTT assay on Human Periodontal Ligament Fibroblast (HPDLF) cells, the 4-hydrazinothiazole derivatives were screened for cytotoxicity in an in vitro cytotoxicity investigation. The 4-hydrazinothiazole compound 6b bearing an isopropylidene-hydrazino group demonstrated a strongly potent cytotoxicity against CAKI1 (IC50 = 1.65±0.24 μM) and A498 (IC50 of 0.85±0.24 μM). Furthermore, the chloroacetyl-containing thiazole compound 7a has displayed efficient inhibition of growth against the test cell lines CAKI1 and A498 at low micromolar IC50 of 0.78 and 0.74 μM, respectively.

Formylation reactions of N-protecting 2-Amino-4-phenyl thiazole compounds

The Vilsmeier Haack formylation reactions of 4-phenyl-N-N'-benzoyl and 4-phenyl-N-substituted (N-sulphonyl and N-phenyl)-2-aminothiazole molecules with POCl3/DMF were studied. The Crystal (6) ((E)-N'-(5-formyl-4-phenylthiazol-2-yl)-N,N-dimethylformimid amide) and crystal (14) (N-phenyl-N-(4-phenylthiazol-2-yl)formamide) molecules were obtained in the formylating reactions of N,N’-benzoyl, N-sulphonyl protecting group 4-phenyl thiazole molecules. In the N-phenyl substituted thiazole compound, an aldehyde functional group is added to the amine group instead of the thiazole ring to form the N-phenyl-N-(4-phenylthiazol-2-yl)formamide molecule. All compounds have been synthesized and characterized by FT-IR, 1H NMR, 13C NMR techniques, and X-ray structure analysis. These molecules demonstrate O,S-syn conformation.

Synthesis of Few New Carrier Polymers Derived from 2-hydrazinylbenzo[d]thiazole

2-hydrazinylbenzo[d]thiazole compound [1] is produced from reaction of 2-mercapto-benzothiazole with hydrazine hydride in ethanol. Compound [1] reacted with maleic anhydride in DMF to produce (Z)-4-(2-(benzo[d] thiazol-2yl) hydrazinyl)-4-oxobut-2-enoic acid [compound (2)]. While the treatment of compound [2] with the ammonium persulfate (NH4)2S2O8 (as the initiator) in order to produce compound [3], then compound [3] reacted with thionyl chloride in benzene to produce compound [4], finally compound [4] reaction with various drugs: cephalexin, amoxicillin, sulfamethizole, elecoxib obtained polymers [5–8]. The structure of synthesized compounds identified by spectral data: fourier transform infrared (FTIR) and proton nuclear magnetic resonance (1HNMR) spectroscopy. The polymers [5–8] have been screened for their antibacterial activities against Staphylococcus aureus (G+), Escherichia coli (G-) and compared with the drug (amoxicillin). The anticancer activity (Hep G2 (human liver cancer cell line) of some prepared polymers were also studied.

2-Amino thiazole derivatives as inhibitors of some metabolic enzymes: An in vitro and in silico study.

The thiazole derivatives are desirable compounds in the evaluation of their biological activities such as antiprotozoal antibacterial, antifungal, antituberculosis. Considering the medical application potential of 2-amino thiazole compounds, we aimed to determine the effects of 2-amino thiazole derivatives on the activities of carbonic anhydrase I-II isoenzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among the chemicals we used in our study, 2-amino-4-(4-chlorophenyl)thiazole compound exhibited the best inhibition against hCA I with Ki of 0.008 ± 0.001μM. The 2-amino-4-(4-bromophenyl)thiazole compound exhibited the best inhibition against hCA II, AChE, and BChE with Ki of 0.124 ± 0.017, 0.129 ± 0.030, and 0.083 ± 0.041μM, respectively. Molecular docking analysis showed that compound 2-amino-4-(5,6,7,8-tetrahydro-2-naphthyl)thiazole had the highest inhibitory potency against hCA I, hCA II, AChE, BChE with the estimated binding energy of -6.75, -7.61, -7.86, -7.96kcal/mol, respectively.

Thiazole-Formulated Azomethine Compound for Three-Way Detection of Mercury Ions in Aqueous Media and Application in Living Cells

Heavy metal ions are extremely poisonous and cause long-term harm to living organisms. Among these ions, mercury is the most toxic metal and has no notorious purpose in the human body. In this regard, an elegant azomethine thiazole compound AM1 was synthesized, and it was found to be highly sensitive to three-way detection of mercury ions with detection limits of 0.1126 × 10–9 M (FL) and 0.64 × 10–6 M (UV–vis). AM1 highlighted the capability to detect mercury ions through the colorimetric method, the fluorometric method, and via the naked eye in three-way detection. In addition, the structure of AM1 was confirmed by single-crystal X-ray diffraction studies and crystallized in a monoclinic crystal system with a P21/c space group, and it shows numerous noncovalent interactions in the crystal packing. The high sensitivity of AM1 to Hg2+ ions was imputed to the quenching mechanism and was estimated by Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (1H-NMR), high-resolution mass spectrometry (HRMS), ultraviolet–visible (UV–vis) absorbance, fluorescence (FL) emission, Job’s plot, B-H plot, and DFT calculation. Naked eye color change of AM1 solution to yellow and turn-off FL by the addition of mercury ion is due to complex formation. In addition to mercury ions, the sensor displayed a new absorption peak at around 240 nm. Furthermore, an AM1-coated test strip is used as the solid support sensor, and real-time detection of Hg2+ ions in the HeLa cell line by fluorescence microscopy is performed.

The role of thiazole acetate derivatives on isolated heart and blood vessels in experimental rats

Background and objectivesThough various drugs are available in the market for cardiovascular diseases, search for an efficacious and patient friendly drug is an ongoing process. The effect of synthesized thiazole compounds on isolated rat heart and isolated rat blood vessel to determine their potential as newer therapeutic agents. Materials and methodsSix thiazole acetate compounds were examined for their function on isolated heart and blood arteries utilizing standardized experimental models after being characterized and identified in the laboratory. Anesthetized Wistar albino rats' hearts were removed and placed on a Langendorff setup. The percentage change in developed tension and heart rate owing to injecting each thiazole acetate compound in the developed tension and heart rate were seen and recorded in an isolated heart that was mounted in a retrograde fashion using Krebs Henseleit solution. Similarly, anesthetized rats' thoracic aortas were separated, and responses to the standard drug phenylephrine and different thiazole acetate derivatives were examined. The pharmacological effect of the specific thiazole compound was determined by the percentage change in contractile response. ResultEach of the six thiazole acetate derivatives was injected at 1 nM, 10 nM, 100 nM, 1 M, 10 M, and 100 M concentrations. All six (T1 to T6) chemicals investigated in the present study had no significant effect on developed tension or heart rate. There was a nosignificant change in the percentage contraction after injecting 1 nM 3 nM,10 nM, 30 nM, 100 nM, 300 nM, 1 M, 3 M, 10 M, and 30 M,100 M,300 M (cumulative dose) of T1, T3, T4, T5, and T6, while T2 (- ethyl-4-methyl-2-aminothiazole) showed contractile effect in the form of vasoconstrictor activity, which was 30 % of that produced by phenylephrine. Interpretation and conclusionThiazole acetate derivatives did not show any cardiovascular effects except ethyl-4-methyl-2-aminothiazole, which showed a slight vascular contractile response as compared to phenylephrine. A more thorough examination of the utilization of thiazole derivatives is required to establish their potential significance in the cardiovascular system.

In Vitro Inhibition Effects of 2-Amino Thiazole Derivatives on Lactoperoxidase Enzyme Activity

Lactoperoxidase (LPO E.C. 1.11.1.7) is a member of the peroxidase family and is an important glycoprotein containing heme group in its structure and showing the antimicrobial effect on disease causing microorganisms in the digestive system of newborn babies. Thiazoles are the simplest members of heterocyclic compounds containing nitrogen and sulfur atoms in their structure. Many active pharmaceutical substances such as vitamin B1, penicillin, and those obtained by synthesis, contain a thiazole ring. It is desirable to evaluate the biological activities of thiazole derivatives, such as antiprotozoal antibacterial, antifungal, antituberculosis, and anthelmintic, with emphasis on their potential medical applications. The aim of this study was to determine the in vitro inhibition profiles of 2-amino thiazole derivatives against bovine LPO enzyme. In this study it was determined that all amino thiazole derivatives inhibited the LPO enzyme competitively. When the results were compared with each other, the 2-Amino-4-(4-chlorophenyl) thiazole compound showed the best inhibition effect against LPO with the Ki value of 250±100 nM.

Synthesis and Structural Confirmation of the Thiazole Alkaloids Derived from Peganum harmala L.

Peganumal A and B are thiazole alkaloids isolated from the seeds of Peganum harmala L. Thiazole moieties are rarely found in natural products, but diverse compounds possessing thiazole moieties have attracted attention owing to their broad range of biological activities. Peganumals are the first natural thiazole compounds isolated from the genus Peganum. It was difficult to define the exact structure of peganumal A via spectroscopic analysis. In this paper, we report the first total synthesis of peganumal A and B. The 5-benzylthiazole skeleton possessing methyl or hydrogen at the 2-position of the peganumals was efficiently constructed via the Hantzsch thiazole synthesis of the α-bromoaldehyde intermediate. Moreover, the spectral data of the synthetic 2H–thiazole compound were identical to those previously reported for peganumal A. The synthesis allowed the confirmation of the structure of peganumal A.

Synthesis and characterization of new thiazole-based Co(II) and Cu(II) complexes; therapeutic function of thiazole towards COVID-19 in comparing to current antivirals in treatment protocol

Two thiazole-based complexes were prepared from Co(II) and Cu(II) ions. The new ligand and its complexes were fully characterized by analytical and spectral techniques. The ligand behaved as a neutral tridentate in its keto-form towards the metals via O(8), O(10) and O(18) atoms. This was suggested based on the lower shift of υ(CHO), υ(CO)amide and υ(CO) vibrations. The electronic transitions in Co(II)-HL and Cu(II)-HL complexes displayed d-d- transitions which belong to 4T1g→4A2g(F) & 4T1g(F)→4T1g (P) and 2Eg →2T2g, in the two complexes, respectively. ESR spectrum of Cu(II)-HL complex displayed g-factor by the following order; g//(2.1740)>g⊥(2.0935)>2.0023, which agrees with octahedral geometry. The geometry optimization was executed by DFT/B3LYP method under valence double zeta polarized basis set (6–31G*), to confirm the structural forms and the mode of bonding. The orientation and the charges of O(8), O(10) and O(18) atoms, support the coordination of the ligand in its keto-form with the metal ions. Pharmacophore profiles were obtained regarding thiazole ligand and other recommended drugs (arbidol, avigan and idoxuridine) that used in treatment protocol of COVID-19 pandemic. Also, query was run in MolPort-library to obtain antiviral analogues, to broaden the search for an effective treatment. Three analogues were obtained for arbidol, avigan and idoxuridine drugs, which have the following numbers; MolPort-047-605-644, MolPort-004-768-508 and MolPort-028-750-709, respectively. Moreover, molecular docking was carried out to obtain all interaction details and rank the efficiency of thiazole compound versus the three antivirals in their interaction with the two COVID-19 proteins. The outcomes suggested the significant antiviral activity of idoxuridine and thiazole (enol-form), which not reach to eliminate the pandemic exactly. While, arbidol and avigan did not have an effective antiviral role, although they still used in COVID-19 treatment protocol.

Enantiomeric Separation of New Chiral Azole Compounds.

Twelve new azole compounds were synthesized through an ene reaction involving methylidene heterocycles and phenylmaleimide, producing four oxazoles, five thiazoles, and one pyridine derivative, and ethyl glyoxylate for an oxazole and a thiazole compound. The twelve azoles have a stereogenic center in their structure. Hence, a method to separate the enantiomeric pairs, must be provided if any further study of chemical and pharmacological importance of these compounds is to be accomplished. Six chiral stationary phases were assayed: four were based on macrocyclic glycopeptide selectors and two on linear carbohydrates, i.e., derivatized maltodextrin and amylose. The enantiomers of the entire set of new chiral azole compounds were separated using three different mobile phase elution modes: normal phase, polar organic, and reversed phase. The most effective chiral stationary phase was the MaltoShell column, which was able to separate ten of the twelve compounds in one elution mode or another. Structural similarities in the newly synthesized oxazoles provided some insights into possible chiral recognition mechanisms.

APPLICATION OF QUANTUM CHEMICAL, NOISE AND THE ELECTROCHEMICAL FREQUENCY MODULATION TO INVESTIGATE THE ADSORPTION AND CORROSION INHIBITION BEHAVIOR OF 2-AMINO-6-HYDROXYBENZOTHIAZOLE FOR STEEL API X80 IN ACIDIC SOLUTION

Different theoretical, electrochemical and surface techniques were applied to study the corrosion inhibition effects of 2-Amino-6-hydroxybenzothiazole in 5% HCl solution. The density functional theory was carried out and quantum chemical factors like the energy gap, energy of highest occupied molecular orbital, the energy of lowest unoccupied molecular orbital, the fraction of electron transferred, and Mulliken charges have been calculated. In addition, according to quantum calculation, S atom in 2-Amino-6-hydroxybenzothiazole indicated more tendency for electrophilic attack in adsorption. The main reason for high inhibition efficiencies in very low concentrations is the planar and simplicity of inhibitor structure which leads to increasing the efficiency of adsorption by functional group especially sulfur. Electrochemical frequency modulation and potentiodynamic polarization indicated that this material has excellent inhibiting features in very low concentrations. The influence of DC trend on the explanation of electrochemical noise data was evaluated by polynomial fitting and the optimum polynomial order m=4 was obtained. Noise resistance and the inhibition efficiency was calculated and compared in different methods. The theory of shot noise in frequency domain was used to obtain the electrochemical event charge. The corroded surface of steel in the absence and existence of thiazole compound was studied by Atomic force microscopy.

Computational and Experimental Study onthe Adsorption and Inhibition Effects of 1,3-Benzothiazol-6-ol on the Corrosion ofSteel X80 in Acidic Solution

Abstract In this work, the adsorption and inhibition behavior of 1,3-benzothiazol-6-ol were investigated by computational and experimental techniques for steel X80 corrosion in acidic solution. The density functional theory was carried out and quantum chemical factors like the energy gap, energy of highest occupied molecular orbital, the energy of lowest unoccupied molecular orbital, the fraction of electron transferred, and Mulliken charges have been calculated. In addition, according to quantum calculation, S atom in 1,3-benzothiazol-6-ol indicated more tendency for electrophilic attack in adsorption. The main reason for high inhibition efficiencies in very low concentrations is the planar and simplicity of inhibitor structure which leads to increasing the efficiency of adsorption by functional group especially sulfur. Electrochemical frequency modulation and potentiodynamic polarization indicated that this material has excellent inhibiting features in very low concentrations. The influence of DC trend on the explanation of electrochemical noise data was evaluated by polynomial fitting and the optimum polynomial order m = 5 was obtained. Noise resistance and the inhibition efficiency was calculated and compared in different methods. The theory of shot noise in frequency domain was used to obtain the electrochemical event charge. The corroded surface of steel in the absence and existence of thiazole compound was studied by Atomic force microscopy.

Multi-stimuli-responsive tetraphenylethene-based thiazole compound: Time-dependently enhanced blue-shift emission, reversible acidichromism and mechanochromism

A new tetraphenylethene-based thiazole compound (TPEB-B) was designed and synthesized, which exhibits multi-stimuli-responsive properties and AIE behavior. TPEB-B exhibits dynamic water-stimuli-responsive properties. When large amount of water is injected into the THF solution of TPEB-B (≥70%), the mixture exhibits gradually enhanced blue-shift emission accompanied by emission color changes from weak aquamarine blue to intense blue emission with increasing standing time. Moreover, TPEB-B exhibits reversible acidichromism behavior. When TPEB-B is exposed to trifluoroacetic acid (TFA), the initial blue emission immediately changes into yellowish green emission that will convert back into initial blue emission as it exposed to triethylamine (TEA). In addition, TPEB-B also exhibits reversible mechanochromism. Upon grinding with a pestle, the intense blue emission of TPEB-B transforms into yellowish green emission that will turn into the original blue emission when the ground TPEB-B is fumed with DCM vapor. Such interesting and multi-stimuli-responsive behaviors make TPEB-B a potential material in anti-counterfeiting and other fields.

Density Functional Theory and Electrochemical Noise Analysis of Corrosion Inhibition Behavior of N,N '-bis(1-(3,5-dihydroxyphenyl)ethylidene)propane-1,3-diamine on Steel in HCl Solution

The inhibition effect of N,N ′-bis(1-(3,5-dihydroxyphenyl)ethylidene)propane-1,3-diamine was studied on steel corrosion in 1 M hydrochloric acid solutions. The density functional theory was applied to calculate quantum chemical parameters such as the highest occupied molecular orbital energy, the lowest unoccupied molecular orbital energy, electron affinity, global electrophilicity index, the fraction of electron transferred, global nucleophilicity index, and Mulliken charges. According to quantum calculation, the diamine compound showed high interaction and effective adsorption on steel surface and high inhibition efficiencies and therefore nitrogen atoms of inhibitor indicated more tendencies for the electrophilic effect in the adsorption. Electrochemical impedance and potentiodynamic polarization indicated that this material has excellent inhibiting features in very low concentrations. The influence of DC trend on the explanation of electrochemical noise data was evaluated by polynomial fitting and the optimum polynomial order m = 4 was obtained. Noise resistance and the inhibition efficiency was calculated and compared in different methods. The theory of shot noise in frequency domain was used to obtain the electrochemical event charge. The corroded surface of steel in the absence and existence of thiazole compound was studied by Atomic force microscopy.

Increasing the potential of cell-penetrating peptides for cancer therapy using a new pentagonal scaffold

Cancer treatment is one of the major fields of interest for the scientific community. Investment in cancer research is costly but essential to provide patients with more effective and safe treatments. In this project, we describe the synthesis and characterization of new thiazole derivatives coupled to CPP2, a cell-penetrating peptide (CPP) reported for colon cancer cells. Using a human adenocarcinoma-derived cell line (Caco-2), these new CPPs were evaluated for antiproliferative (3H-thymidine incorporation) and cytotoxic effect (extracellular lactate dehydrogenase activity). One of these derivatives, the BTZCA thiazole compound and its peptide-conjugated (BTZCA-CPP2) also showed the ability to decrease tumour cell viability and proliferation, with potential cytotoxic effect against human breast cancer MCF-7 cells. Then, cytotoxicity studies were developed against J774, L929 and THP1 cell lines and this new family showed no significant cytotoxicity, when compared to their counterparts alone (BTZCA and CPP2). The use of smaller CPP conjugated with this family of derivatives can be also considered in future for the development of new drugs to cancer therapy.

A new AIE and TICT-active tetraphenylethene-based thiazole compound: Synthesis, structure, photophysical properties and application for water detection in organic solvents

A new thiazole derivative 2-(4-nitrophenyl)-6-(1,2,2-triphenylvinyl)benzo[d]thiazole (TBTNO2) based on tetraphenylethene (TPE) was designed and synthesized. The structure has been fully characterized by NMR, MS, elemental analysis and single crystal X-ray diffraction analysis, and its properties were analyzed by spectroscopy and theoretical study. Under the combined action of twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE), TBTNO2 exhibits extraordinary “on–off–on” optical switching property accompanied by changes of the emission color with the addition of water into its tetrahydrofuran (THF) and dioxane (Diox) solution. Interestingly, TBTNO2 is highly sensitive to trace water in organic solvents such as THF, Diox, ethyl acetate (EA) and diethyl ether (DEE), making TBTNO2 be a highly sensitive fluorescent sensor for water detection with a detection limit of 0.019% for THF, 0.076% for Diox, 0.092% for EA and 0.103% for DEE (v/v), respectively. The measuring results of trace water in real samples using TBTNO2 as the sensor are well consistent with those of the Karl Fischer method. TBTNO2 can be employed as a sensitive indicator to monitor trace water during the drying process for organic solvents conveniently. In addition, compound TBTNO2 exhibits large Stokes shift and significant solvatochromic effect.

“2-(4-Fluorobenzamido)-4-methylthiazole-5-carboxylic acid” a novel thiazole compound, ameliorates insulin sensitivity and hyperlipidaemia in streptozotocin-induced diabetic rats: Plausible role of inflammatory and oxidative stress markers

Emerging evidence suggests that thiazole compounds are of great interest due to their protective effect against DM. Protective effects of thiazole derivatives against hyperglycemia have been demonstrated in earlier in vitro and in vivo studies. Previously, anti-oxidant and free radical scavenging activities of 2-(4-Fluorobenzamido)-4-methylthiazole-5-carboxylicacid, a newly developed thiazole derivative (NDTD), have been well-documented. Current study investigated the pharmacological effect of NDTD on hyperglycaemia, insulin sensitivity, lipid profile, anti-inflammatory and oxidative stress markers in an animal model. T2DM was induced in neonatal rats using single i.p. injection of STZ at a dose of 100mg/kg. As a result, significant increase in serum glucose, insulin and HOMA-IR, lipid and pro-inflammatory cytokines levels were observed in STZ diabetic rats compared to normal control rats. Administration of NDTD for 4 weeks reversed the increased levels of above mentioned parameters to normal. Increased serum TG, TC, LDL-C and VLDL-C levels were significantly lowered, while reduction of serum HDL-C was alleviated after administration of NDTD. In addition, NDTD attenuated oxidative stress markers by increasing levels of GSH, CAT, SOD and lowering the level of MDA. Similarly, NDTD showed its pharmacological effects against hepatic and renal injury markers via restoring the alleviated level of ALT, AST, BUN, CRE and uric acid. In addition, all the results obtained from the biochemical estimations were supported by the histopathological examination. Pancreatic histopathological study demonstrated reduction in the size of pancreatic islets as well as the number of β-cells, per islet in the STZ control group and diabetic rats exposed to NDTD normalized the morphology of islets. Furthermore, histopathological study of liver suggests the protective role of NDTD against hepatic injury, as diabetic rats exposed with NDTD shows significantly reduction in inflammation and lesion as compared to STZ control rats. Our findings concluded, NDTD attenuated hyperglycaemia, glucose intolerance and insulin resistance through its anti-oxidant and anti-inflammatory effects. Thus, we suggest NDTD as potential therapeutic candidate for T2DM. In addition, the current study also investigated the beneficial effects of NDTD against inflammation, hyperlipidemia, renal and hepatic injury.

A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of oral COH29, a novel ribonucleotide reductase (RNR) inhibitor in adult patients (pts) with advanced solid tumors.

TPS2600 Background: Human RNR catalyzes the rate-limiting step in the formation of deoxyribonucleotide triphosphates (dNTPs) necessary for DNA repair and replication. Rapidly dividing tumor cells are especially sensitive to RNR inhibition due to elevated dNTP requirements. Overexpression of the RNR RRM2 subunit is also associated with neoplasia, metastasis, and poor prognosis. COH29 is an aromatically substituted thiazole compound that is a novel small molecule inhibitor of RNR activity, and exhibits unique mechanisms and target specificity that overcomes the weaknesses of other small molecule RNR inhibitors. Preclinically, it is more potent than hydroxyurea and gemcitabine, and is not associated with iron chelating-related toxicities such as hypoxia. Cell lines deficient in BRCA1 also exhibit greater sensitivity to COH29 than BRCA1 wildtype cell lines, implicating inhibition of DNA repair mechanisms in line with PARP inhibitors. Methods: In this Phase I, single site, dose escalation, safety study pts will receive oral COH29 twice a day for 21 days of a 28-day cycle. Eligible pts are age ≥ 18 years, ECOG ≤ 2, able to take oral medication, have adequate organ and marrow function, and diagnosed with any solid tumor refractory to standard therapies. Dose escalation will be pursued utilizing a Simon’s accelerated titration design, which allows skipping of dose levels (dose doubling) during the accelerated dose-finding phase. Primary objectives are to determine the maximum tolerated dose of COH29, toxicities per CTCAEv4, and PKs. Secondary objectives include assessment of objective response per RECIST 1.1 every 2 cycles. PD assessment includes measurement of plasma CK18 levels to determine degree of cellular apoptosis, evaluation of dNTP pool levels in peripheral blood mononuclear cells (PBMCs) to evaluate RNR inhibition, as well as measurement of PAR expression in PBMCs to assess PARP inhibition. Quantitation of tumor RRM2 expression using dual-color immunohistochemistry will be explored as a predictive biomarker of anti-tumor response to COH29. Clinical trial information: NCT02112565.