Development, synthesis and validation of improved c-Myc/Max inhibitors.

The pathophysiological foundations of various diseases are often subject to alteration through the utilization of small compounds, rendering them invaluable tools for the exploration and advancement of novel therapeutic strategies. Within the scope of this study, we meticulously curated a diverse library of novel small compounds meticulously designed to specifically target the c-Myc/Max complex. We conducted in vitro examinations of novel c-Myc inhibitors across a spectrum of cancer cell lines, including PANC1 (pancreatic adenocarcinoma), MCF7 (breast carcinoma), DU-145 (prostate carcinoma), and A549 (lung cancer). The initial analysis involved a 25 µM dose, which enabled the identification of potent anticancer compounds effective against a variety of tumour types. We identified c-Myc inhibitors with remarkable potency, featuring IC50 values as low as 1.6 µM and up to 40 times more effective than the reference molecule in diminishing cancer cell viability. Notably, c-Myc-i7 exhibited exceptional selectivity, displaying 37-fold and 59-fold preference for targeting prostate and breast cancers, respectively, over healthy cells. Additionally, we constructed drug-likeness models. This study underscores the potential for in vitro investigations of various tumour types using novel c-Myc inhibitors to yield ground-breaking and efficacious anticancer compounds.

Unveiling potent Schiff base derivatives with selective xanthine oxidase inhibition: In silico and in vitro approach.

This research describes the synthesis by an environmentally-friendly method, microwave irradiation, development and analysis of three novel and one previously identified Schiff base derivative as a potential inhibitor of bovine xanthine oxidase (BXO), a key enzyme implicated in the progression of gout. Meticulous experimentation revealed that these compounds (10, 9, 4, and 7) have noteworthy inhibitory effects on BXO, with IC50 values ranging from 149.56 µM to 263.60 µM, indicating their good efficacy compared to that of the standard control. The validation of these results was further enhanced through comprehensive in silico studies, which revealed the pivotal interactions between the inhibitors and the catalytic sites of BXO, with a particular emphasis on the imine group (-C = N-) functionalities. Intriguingly, the compounds exhibiting the highest inhibition rates also showcase advantageous ADMET profiles, alongside encouraging initial assessments via PASS, hinting at their broad-spectrum potential. The implications of these findings are profound, suggesting that these Schiff base derivatives not only offer a new vantage point for the inhibition of BXO but also hold considerable promise as innovative therapeutic agents in the management and treatment of gout, marking a significant leap forward in the quest for more effective gout interventions.

Exploring the Anti-Cancer Potential of Hispidin: A Comprehensive in Silico and in Vitro Study on Human Osteosarcoma Saos2 Cells.

Hispidin was initially discovered in basidiomycete Inonotus hispidus (Bull.) P. Karst and this extraordinary compound possesses immense potency and can be extracted from the wild mushroom through specialized bioreactor cultivation techniques. In our study, we isolated it from Inonotus hispidus (Bull.) P. Karst., with a yield of 3.6 %. We identified and characterized hispidin through the implementation of spectroscopic techniques such as FTIR, NMR, and MS. Additionally, we utilized Thermogravimetric Analysis for thermal characterization of the compound. Computational studies based on DFT were performed to investigate the molecular structure, electronic properties, and chemical reactivity of hispidin. PASS analysis for hispidin demonstrated that 19 of them are anti-neoplastic activities. The Pharmacology prediction of hispidin confirm that it is not toxic, non-carcinogenesis with a good human intestinal absorption. The effect of hispidin on the viability of bone cancer cells was evaluated by MTT assay. The results showed that hispidin significantly reduced SaoS2 cell viability in a dose-dependent manner. Molecular docking was carried out using five targets related to bone cancer to determine the interactions between hispidin and the studied proteins. The results demonstrate that hispidin is a good inhibitor for the five targets. Dynamic simulation shows a good stability of the complex hispidin-protein.

Cryogenic X-ray crystallographic studies of biomacromolecules at Turkish Light Source "Turkish DeLight".

X-ray crystallography is a robust and powerful structural biology technique that provides high-resolution atomic structures of biomacromolecules. Scientists use this technique to unravel mechanistic and structural details of biological macromolecules (e.g., proteins, nucleic acids, protein complexes, protein-nucleic acid complexes, or large biological compartments). Since its inception, single-crystal cryocrystallography has never been performed in Türkiye due to the lack of a single-crystal X-ray diffractometer. The X-ray diffraction facility recently established at the University of Health Sciences, Istanbul, Türkiye will enable Turkish and international researchers to easily perform high-resolution structural analysis of biomacromolecules from single crystals. Here, we describe the technical and practical outlook of a state-of-the-art home-source X-ray, using lysozyme as a model protein. The methods and practice described in this article can be applied to any biological sample for structural studies. Therefore, this article will be a valuable practical guide from sample preparation to data analysis.

Development of novel 1,2,4-triazole containing compounds with anticancer and potent anti-CB1 activity.

There is still an unmet need for novel and improved anti-cancer compounds. Nitrogen atoms have heterocyclic ring moieties, which have been shown to have powerful anticancer properties in both natural and synthetic derivatives. Due to their dipole character, hydrogen bonding capacity, rigidity and solubility, 1,2,4-triazoles are particularly effective pharmacophores, interacting with biological receptors with high affinity. Thus, novel 1,2,4-triazole-containing molecular derivatives were synthesized using green chemistry methods, microwave irradiation and ultrasonication, and these methods' operational simplicity and maximum greener synthetic efficiency with green chemistry metrics calculations will be attractive for academic and industrial research and tested against three distinct human cancer cell lines including PANC1 (pancreatic cancer), DU145 (prostate cancer), MCF7 (breast cancer) and one fibroblast cell line (HDF). Here, we showed that compounds 5e and 5f were similar to CB1 antagonists in structure, binding affinity and poses. In addition, compounds 5e-g decreased the viability of pancreatic and prostate cancer cells, albeit with cytotoxicity to HDF cells. The IC50 values for PANC1 cells were between 5.9 and 7.3 µM for compounds 5e-g. Cell cycle analysis showed that the effect of compounds 5e-g in cancer cell growth was largely due to cell cycle arrest at S-phase. In sum, novel 1,2,4-triazole-containing compounds with anticancer and potent anti-CB1 activity have been developed.Communicated by Ramaswamy H. Sarma.

Piperazin incorporated Schiff Base derivatives: Assessment of in vitro biological activities, metabolic enzyme inhibition properties, and molecular docking calculations.

The cytotoxic activities of the compounds were determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) method in human breast cancer (MCF-7), human cervical cancer (HeLa), and mouse fibroblast (L929) cell lines. The compounds MAAS-5 and four modified the supercoiled tertiary structure of pBR322 plasmid DNA. MAAS-5 showed the highest cytotoxic activity in HeLa, MCF-7, and L929 cells with IC50 values of 16.76 ± 3.22, 28.83 ± 5.61, and 2.18 ± 1.22 µM, respectively. MAAS-3 was found to have almost the lowest cytotoxic activities with the IC50 values of 93.17 ± 9.28, 181.07 ± 11.54, and 16.86 ± 6.42 µM in HeLa, MCF-7, and L929 cells respectively at 24 h. Moreover, the antiepileptic potentials of these compounds were investigated in this study. To this end, the effect of newly synthesized Schiff base derivatives on the enzyme activities of carbonic anhydrase I and II isozymes (human carbonic anhydrase [hCA] I and hCA II) was evaluated spectrophotometrically. The target compounds demonstrated high inhibitory activities compared with standard inhibitors with Ki values in the range of 4.54 ± 0.86-15.46 ± 8.65 nM for hCA I (Ki value for standard inhibitor = 12.08 ± 2.00 nM), 1.09 ± 0.32-29.94 ± 0.82 nM for hCA II (Ki value for standard inhibitor = 18.22 ± 4.90 nM). Finally, the activities of the compounds were compared with the Gaussian programme in the B3lyp, HF, M062X base sets with 6-31++G (d,p) levels. In addition, the activities of five compounds against various breast cancer proteins and hCA I and II were compared with molecular docking calculations. Also, absorption, distribution, metabolism, excretion, and toxicity analysis was performed to investigate the possibility of using five compounds as drug candidates.

Recent advances in triazoles as tyrosinase inhibitors.

The tyrosinase enzyme, which is widely found in microorganisms, animals and plants, has a significant position in melanogenesis, plays an important role in undesirable browning of fruits and vegetables, antibiotic resistance, skin pigment formation, sclerotization of cuticle, neurodegeneration, etc. Therefore, with the wide potential application fields of tyrosinase in food, agriculture, cosmetics and pharmaceutical industries, which has become the target enzyme for the development of therapeutic agents such as antibrowning, anticancer, antibacterial, skin whitening, insecticides, etc., a large number of synthetic tyrosinase inhibitors have been widely reported in recent years. The triazole ring, which has a broad spectrum of biological action, is of increasing interest in the synthesis of new tyrosinase inhibitors. In this review, tyrosinase inhibition effects, structure-activity relationships, enzyme inhibition kinetics and mechanisms of action of 1,2,3- or 1,2,4-triazole derivatives were investigated. The data gathered is anticipated to supply rational guidance and an influential strategy for the development of novel, potent and safe tyrosinase inhibitors for better practical application in the future.

Synthesis and evaluation of the antioxidant and anti-tyrosinase activities of thiazolyl hydrazone derivatives and their application in the anti-browning of fresh-cut potato.

Tyrosinase is a key enzyme in the biosynthesis of melanin, which is responsible for the browning of foods as well as many skin disorders. In order to develop new anti-browning agents with dual antioxidant and anti-tyrosinase capacities, a series of 30 thiazolyl hydrazone derivatives were synthesized. Among the molecules prepared, 6 and 30 were found to be the most potent tyrosinase inhibitors with IC50 values ​​comparable to that of kojic acid. Interestingly, 6 also has the highest radical scavenging activity among the prepared molecules. The inhibition kinetics study indicated that 6 is a non-competitive inhibitor while 30 inhibits tyrosinase competitively. The anti-browning assay of fresh-cut potato slices revealed that 6 and 30 are potent anti-browning agents with a capacity as high as kojic acid. The mechanisms of free radical scavenging and tyrosinase inhibition have been fully investigated in silico using computational kinetics, molecular docking, and molecular dynamics simulations.

Synthesis of novel pancreatic lipase inhibitors: Biological investigation and in silico studies.

The targeted compounds which are Schiff base derivatives were prepared by reaction of 6-(4-phenyl-piperazin-1-yl)pyridine-3-ylamine with 2-hydroxy and 2,6-dichloro benzaldehyde. These compounds were isolated, purified and then spectrally characterized via FT-IR, 1H and 13C NMR, LC MS TOF, and TGA analysis where strong proofs confirmed the formation of the targeted product. The biological activity, which is pancreatic porcine lipase inhibition, of the compounds was investigated and Orlistat was used as standard drug. The compound 3 was found to be as potent as orlistat against PL enzyme with an IC50 value of 0.50 µM. The molecular docking studies were performed for both obtained compounds and orlistat against active side of porcine pancreatic lipase. Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analyzes were performed for pancreatic porcine lipase with compound 3, which showed potent inhibition according to the results of in vitro studies. Furthermore, The ADME and toxicity analysis of the compounds were examined using web-based online platforms, SwissADME and pkCSM. In the light of biological activity and in silico studies, the compound 3 can be a potential drug candidate with further studies.Communicated by Ramaswamy H. Sarma.

The role of machine learning method in the synthesis and biological investigation of heterocyclic compounds.

Machine learning (ML) methods have attracted increasing interest in chemistry as in all fields of science in recent years. This method is of great importance for the design of targeted bioactive compounds, especially by avoiding loss of time, money, and chemicals. There are lots of online web-based platforms such as LibSVM and OCHEM for the application of ML methods. In this paper, it has been examined the literature data on the activity predictions of heterocyclic compounds, biological activity results such as antiurease, HIV-1 Integrase, E. Coli DNA Gyrase B, and antifungal, pharmacophore-based studies, synthesis, and finding possible inhibitors using different machine learning methods.

Synthesis, characterization, DFT calculation, antioxidant activity, ADMET and molecular docking of thiosemicarbazide derivatives and their Cu (II) complexes.

In this work, new thiosemicarbazides (ECA-1, ECA-2) and their Cu (II) complexes (ECA-1-Cu, ECA-2-Cu) were synthesized and their structures were characterized by 1H NMR, 13C NMR, FT-IR, LC-MS, UV-Vis, and thermogravimetric analysis methods. Also, the surface morphology of the all compounds were examined by SEM (Scanning Electron Microscope). In the second stage, in vitro antioxidant capacity of the obtained compounds was investigated. The evaluation of the antioxidant properties of both synthesized ligands and complexes in this study was carried out by DPPH and FRAP methods. According to the results, both complexes exhibited more antioxidant capacity than the corresponding ligands. When antioxidant effects are compared for DPPH (SC50 = 5.27 ± 0.05 µM) and for FRAP (7845.69 ± 16.75 mmolTE/g), compound ECA-2-Cu appears to have the best inhibition effect. The complexes were found non-electrolytic in nature with melting point of above 250 °C, and electronic spectra and magnetic behavior demonstrated that the complexes were found to be tetrahedral geometry. Further, in silico the ADMET properties which studies are a significant role in improving and predicting drug compounds were calculated using web-based platforms. The theoretical calculations were made using the method of Density Functional Theory (Frontier molecular orbital analyze and Nonlinear optical properties). Also, molecular docking studies were performed to evaluate the binding interactions between the ligand and complex compounds and Human Peroxiredoxin 2. Both in vitro and in silico results indicated that synthesized compounds could act as potent antioxidant agents.

Screening of the small molecule library of Meinox enables the identification of anticancer compounds in pathologically distinct cancers.

Small molecules are widely used for the modulation of the molecular basis of diseases. This makes them the perfect tool for discovering and developing new therapeutics. In this work, we have established a library of small molecules in house and characterized its molecular and druglike properties. We have shown that most small molecules have molecular weights less than 450. They have pharmaceutically relevant cLogP, cLogS, and druglikeness value distributions. In addition, Meinox's small molecule library contained small molecules with polar surface areas that are less than 60 square angstroms, suggesting their potent ability to cross the blood-brain barrier. Meinox's small molecule library was also tested in vitro for pathologically distinct forms of cancer, including pancreatic adenocarcinoma PANC1, breast carcinoma MCF7, and lymphoblastic carcinoma RS4-11 cell lines. Analysis of this library at a dose of 1 µM allowed the discovery of potent, specific or broadly active anticancer compounds against pathologically distinct cancers. This study shows that in vitro analysis of different cancers or other phenotypic assays with Meinox small molecule library may generate novel and potent bioassay-specific compounds.

Recent studies of nitrogen containing heterocyclic compounds as novel antiviral agents: A review.

N-heterocycles are important, not only because of their abundance, but above all because of their chemical, biological and technical significance. They play an important role in biological investigation such as anticancer, antiinflammatory, antibacterial, antiviral, anti-tumor, antidiabetic, etc. In this study, we focused on examining synthesized some 5- or 6-ring N-heterocyclic compounds that showed the antiviral activity in last 5 years, and investigation of these compounds structure-activity relationship studies. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, and pharmacology.

The Importance of Rhodanine Scaffold in Medicinal Chemistry: A Comprehensive Overview.

After the clinical use of epalrestat that contains a rhodanine ring, in type II diabetes mellitus and diabetic complications, rhodanin-based compounds have become an important class of heterocyclic in the field of medicinal chemistry. Various modifications to the rhodanine ring have led to a broad spectrum of biological activity of these compounds. Synthesis of rhodanine derivatives, depended on advenced throughput scanning hits, frequently causes potent and selective modulators of targeted enzymes or receptors, which apply their pharmacological activities through different mechanisms of action. Rhodanine-based compounds will likely stay a privileged scaffold in drug discovery because of different probability of chemical modifications of the rhodanine ring. We have, therefore reviewed their biological activities and structure activity relationship.

4-Quinolone-Carboxamide and Carbothioamide Compounds as Fluorescent Sensors. New Fluorimetric Methods for Cu2+ and Fe3+ Determination in Tap Water and Soil.

Ion sensor properties of the carboxamide and carbothioamide compounds carrying 4-quinolone group were investigated by means of emission spectrometry in methanol-water (1:1). The compounds were selectively complexed with Cu2+, Pd2+, and Fe3+ among many metal ions. The complex stoichiometry and the stability constant were determined by fluorimetric measurements. The carboxamide compound having phenyl group (QPO) showed sensitivity for Fe3+ ion with a linear range between 0.1 and 0.7 mg/L. The new method was applied in the determination of iron in the spiked tap water samples and the sandy-soil reference material. A modified standard addition method was used to remove the matrix effect. Limit of detection was 0.03 mg/L for the Fe3+ determination method. The carboxamide compound with benzyl group (QBO) showed sensitivity for Cu2+ ion with linear range 0-0.4 mg/L. There was no matrix effect for copper determination in the spiked tap water samples. The detection limit of the method for Cu2+ ion was 0.05 mg/L. The quantification limits of the methods were low enough to determine iron and copper amount in drinking water samples according to EPA.

Piperazine-azole-fluoroquinolone hybrids: Conventional and microwave irradiated synthesis, biological activity screening and molecular docking studies.

A series of new 1,2,4-triazole and 1,3,4-oxadiazole derivatives was obtained via several steps sequential reactions of phenyl piperazine. Then, these compounds were converted to the corresponding fluoroquinolone hybrids via one pot three component Mannich reaction. All the reactions were examined under conventional and microwave mediated conditions, and optimum conditions were determined. The effect of different solvents and microwave power on microwave prompted reactions was investigated as well. All the newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR and EI MS spectral techniques. The antimicrobial activity, DNA gyrase and Topoisomerase IV inhibition potentials were performed. The results obtained showed that fluoroquinolone hybrids possess good antimicrobial activity. Moreover, Fluoroquinolone-azole-piperazine hybrids synthesized in the present study displayed excellent DNA gyrase inhibition. To unveil the interaction mode of compounds to receptor, a molecular docking study was performed. With an average least binding energy of -9.5 kcal/mol, all compounds were found to have remarkable inhibitory potentials against DNA gyrase (E. coli).

Synthesis, biological activity and structure activity relationship studies of novel conazole analogues via conventional, microwave and ultrasound mediated techniques.

1,2,4-Triazole derivatives containing a piperazine nucleus (4a-d and 10) were prepared starting from 1-(2-methoxyphenyl)piperazine or ethyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate via several steps. The synthesis of fifteen compounds (7a-l and 13a-c), which can be considered as new analogues of azole class antifungals was performed starting from 1,2,4-triazoles (4a-d and 10) via three steps containing the condensation with 2-bromo-1-(4-chlorophenyl)ethanone, reduction of carbonyl group to alcohol and alkylation of OH group, respectively. All the reactions were examined under conventional, ultrasound and microwave irradiation conditions as green chemistry techniques, and optimum conditions were defined. The newly synthesized compounds were screened for their biological potentials including antimicrobial, antioxidant, antiurease and anti α-glucosidase activities and promising results were obtained. The enzyme inhibitory potentials of these compounds were further validated through molecular docking.

Conventional and microwave prompted synthesis, antioxidant, anticholinesterase activity screening and molecular docking studies of new quinolone-triazole hybrids.

The synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylates (4, 5) was performed via the reaction of corresponding anilines with diethyl ethoxymethylenemalonate under conventional and also microwave promoted conditions. The treatment of 4 and 5 afforded the corresponding hydrazides (6 and 7). These hydrazides were converted to the corresponding carbo(thio)amides (9a-f and 10a-e) which were then subjected to an intramolecular cyclisation leading to the formation of quinolone-triazole hybrids (11a-f and 12a-e). The newly synthesized compounds were screened for their biological activities such as antioxidant capacity (AC) and acetylcholinesterase Activity. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of some novel quinolonederivatives were designed, synthesized, and their inhibitory effects on AChE were evaluated. We obtained our compounds and determined their anticholinesterase activities according to the Ellman's method. 9b and 10c showed the best AChE inhibition with 0.48 ±â€¯0.02 and 0.52 ±â€¯0.07, respectively. Docking studies were performed for the most active compounds (9b, 10c) and interaction modes with enzyme active sites were determined. As a result of these studies, a strong interaction between these compounds and the active sites of AChE enzyme was revealed.

The electrochemical and spectroelectrochemical properties of metal free and metallophthalocyanines containing triazole/piperazine units.

The synthesis and characterization of novel peripherally tetra [1,2,4]-triazole substituted metal-free phthalocyanine and its metal complexes (Zn(II), Ni(II), Pb(II), Cu(II) and Fe(II)) and the investigation of electrochemical and spectroelectrochemical properties of metal-free, Zn(II), Pb(II), Fe(II) phthalocyanines were performed for the first time in this study. Electrochemical characterizations of the complexes were performed with voltammetric and in situ spectroelectrochemical measurements. Voltammetric responses of the complexes supported the proposed structures, since complexes bearing redox inactive Pc ring metal centers just gave Pc based electron transfer reactions, while iron phthalocyanine went to metal based electron transfer reaction in addition to the Pc based ones. Electron withdrawing nature of [1,2,4]-triazole substituents shifted the redox processes toward the positive potentials. All complexes were electropolymerized during the oxidation reactions in dichloromethane (DCM) solvent. Types of the metal center of the complexes altered the electropolymerization reactions of the complexes. Spectra and colors of the electrogenerated redox species of the complexes were also determined with in situ spectroelectrochemical and in situ electrocolorimetric measurements.

Microwave assisted synthesis of some hybrid molecules derived from norfloxacin and investigation of their biological activities.

Norfloxacin was converted to 7-(4-amino-2-fluorophenyl)piperazin derivative (2) via the formation of nitro compound. The synthesis of the norfloxacin derivatives containing 1,3-thiazole or 1,3-thiazolidin moiety was performed from the reaction of 4-chlorophenacylbromide or ethyl bromoacetate with compounds 4-7 obtained starting from 2. 3-Fluoro-4-[4-(2-methoxyphenyl)piperazin-1-yl]aniline (14), 5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-4-phenyl-4H-1,2,4-triazole-3-thiol (18) and {[4-(2-methoxy phenyl)piperazin-1-yl]methyl}-1,3,4-oxadiazol-2-thiol (19) were obtained starting from 1-(2-methoxyphenyl)piperazine by several steps. The treatment of hydrazide (16) with several aldehydes afforded N'-[(2-hydroxyphenyl)methylen]- (20), N'-[(3-hydroxy-4-methoxy phenyl)methylen]- (21) or N'-[1H-indol-3-ylmethylene]-2-[4-(2-methoxyphenyl)piperazin-1-yl]acetohydrazide (22). Then, compounds 14, 18, 19 and 22 were condensed with 7-[4-(chloroacetyl)piperazin-1-yl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3) that was obtained from norfloxacine. All newly synthesized compounds were screened for their antimicrobial activities and some of them exhibited excellent activity. Moreover, one compound was found to have antiurease activity.