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The incidence of neurodegenerative Alzheimer's and Parkinson's diseases is increasing worldwide every day, and treatment options are currently very limited. There is no definitive cure for these diseases, and the drugs available in clinical practice only provide symptomatic relief without halting the progression of neurodegeneration. One commonly employed strategy in the treatment of Alzheimer's and Parkinson's diseases is to return neurotransmitter levels by inhibiting enzymes like cholinesterase (ChE) and monoamine oxidase (MAO). In this research, we focused on investigating the therapeutic potential of 2-[2-(substituted benzylidene)hydrazinyl]-4-(substituted phenyl)thiazole derivatives (2a–2h) by incorporating hydrazine, known for its inhibitory effects on monoamine oxidases, into the structure of molecules that inhibit acetylcholinesterase. Thiazole ring was included in these derivatives due to its reported inhibitory activity against both cholinesterases and monoamine oxidase enzymes. When the enzyme inhibition activities were evaluated, it was determined that compounds 2c, 2d, and 2h showed the highest inhibitory activity against AChE, while compounds 2f and 2h expressed the highest activity against MAO-B. It was determined that compound 2h had the highest inhibitory activity on both AChE (0.030 ± 0.001 μM) and MAO-B (0.048 ± 0.002 μM) and compound 2h was the only compound with conspicuous dual inhibitory activity. Furthermore, molecular docking calculations and molecular dynamics simulations were found to agree with experimental results. [ABSTRACT FROM AUTHOR]

In this study, the synthesis of N‐(5,6‐methylenedioxybenzothiazole‐2‐yl)‐2‐[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a‐3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β‐secretase 1 (BACE‐1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE‐1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified. [ABSTRACT FROM AUTHOR]

Background: Depression is a disease that affects millions of people worldwide, and the discovery and development of effective and safe antidepressant drugs is one of the important topics of psychopharmacology. Objectives: In this study, it was aimed to investigate the antidepressant-like activity potential of tofisopam, an anxiolytic drug with 2,3-benzodiazepine structure, and to elucidate the pharmacological mechanisms mediating this effect. Methods: The antidepressant-like activity of tofisopam was investigated using tail suspension and modified forced swimming tests. Possible interactions of tofisopam with µ- and δ-opioid receptor subtypes were clarified by pharmacological antagonism, molecular docking and molecular dynamics simulation studies. Results: Tofisopam (50 and 100 mg/kg) significantly shortened the immobility time of mice in both the tail suspension and the modified forced swimming tests. The drug, at the same doses, prolonged the duration of swimming and climbing behaviours measured in modified forced swimming tests. A dosage of 25 mg/kg was ineffective. Mechanistic studies showed that the pretreatment with p-chlorophenylalanine methyl ester (serotonin synthesis inhibitor; 4 consecutive days, 100 mg/kg), α-methyl-para-tyrosine methyl ester (catecholamine synthesis inhibitor; 100 mg/kg), naloxonazine (selective µ-opioid receptor blocker, 7 mg/kg) and naltrindole (a selective δ-opioid receptor blocker, 0.99 mg/kg) abolished the anti-immobility effect induced by the 50 mg/kg dose of tofisopam in the tail suspension tests. Our in silico studies supported the behavioural findings that the antidepressant-like effect of tofisopam is mediated by μ- and δ-opioid receptors. Conclusion: This study is the first to show that tofisopam has antidepressant-like activity mediated by the serotonergic, catecholaminergic and opioidergic systems. [ABSTRACT FROM AUTHOR]

• 16 New thiadiazole derivatives were synthesized. • The compound 3d indicated important inhibitory activity against COX-2 enzyme. • Compound 3d inhibits the COX-2 enzyme at a similar rate to celecoxib. • Interaction modes between the COX-2 and compounds 3d were determined by docking studies. • Docking studies for 3d were performed using crystal structures of COX-2 enzyme (PDB ID: 6COX). Currently, selective COX-2 inhibitors are used as a novel alternative approach in the course of pain management due to their reduced adverse that generally occur after COX-1 inhibition by non-selective COX inhibitors. In this work, 16 new thiadiazole derivatives (3a-3p) were designed, synthesized and biologically evaluated for their COX-1 and COX-2 inhibitory potential using the in vitro fluorometric method. The biological evaluation showed that compounds 3c and 3d displayed significant activity against COX-2 with IC 50 values of 0.350±0.015 µM and 0.134±0.004 µM, respectively, making the compound 3d similar in its activity to the reference drug celecoxib (IC 50 =0.132±0.005 µM). Further docking simulation also revealed that the most active derivative (3d) interacted with the enzyme active site in a similar manner to celecoxib. The binding modes of the compound on COX-2 were fully elucidated by molecular dynamics studies. [Display omitted] [ABSTRACT FROM AUTHOR]

• Some novel coumarin derivatives have been synthesized. • The structures of the novel hybrid compounds were determined using spectroscopy techniques. • All of the compounds were tested in vitro for their antimicrobial activity. • Molecular docking and dynamic simulation are used to examine 14α-demethylase (LDM) and thymidylate synthase (TS). • DFT was used to investigate the chemical reactivity characteristics of all novel compounds. The novel series of coumarin derivatives have been synthesized, and the chemical structures of the compounds have been elucidated by 1H NMR, 13C NMR, and LC/MS-IT-TOF spectral data. All compounds were tested on eight bacteria and three fungal species, and for each, the minimum inhibitory concentration (MIC) was calculated. Some of the compounds exhibited good activity against microbial strains. Compound 4e was found to be 2-fold and 4-fold more active against C. parapsilopsis (MIC: 0.97 µg/mL) than standard drugs voriconazole and fluconazole, respectively. Compounds 4a and 4i also show good activity against E. faecalis and E. coli , respectively. Compounds 4e and 4a were used in molecular docking and dynamic simulation to examine on 14α-demethylase (LDM) and thymidylate synthase (TS). Furthermore, using density functional theory at the B3LYP/6–31 G (d, p) level, the chemical reactivity properties of all molecules were examined. Compound 4e in active pocket of lanosterol 14α-demethylase enzyme (C. parapsilopsis , MIC: 0.97 µg/mL). [Display omitted] [ABSTRACT FROM AUTHOR]

The inhibitory effects of 2-thiazolyl hydrazones on monoamine oxidase enzymes are known for a long time. In this study, a new series of 2-thiazolyl hydrazone derivatives were synthesized starting from 6-methoxy-2-naphthaldehyde. All of the synthesized compounds were investigated in terms of their monoamine oxidase (MAO) inhibitory effects and significant results were found. The results showed that compound 2j potently inhibited MAO-A and MAO-B, while compound 2t strongly and selectively inhibited MAO-B compared to standard drugs. Compounds 2k and 2q exhibited selective and satisfying inhibition on MAO-B. In the aromatase inhibition studies of the compounds, it was determined that compounds 2q and 2u had high inhibitory properties. Molecular docking studies on MAO-A, MAO-B, and aromatase enzymes were carried out for the aforementioned compounds. Additionally, molecular dynamics simulation was studied for compound 2q on MAO-B and aromatase complexes. Finally, the Field-based QSAR study was developed and the structure-activity relationship (SAR) was explained. For the first time, dual inhibitors on MAO and aromatase enzyme were investigated together. The aim of this approach is for finding the potential agents that do not cause the cognitive disorders and may even treat neurodegenerative symptoms, thus, the aim was reached successfully. [Display omitted] • New thiazole hydrazone derivatives were synthesized. • MAO and aromatase activity of new compounds were investigated. • Molecular docking and molecular dynamic simulation studies were performed. • It was found a potent dual inhibitor. • The field-based-QSAR model was developed to clarify the SAR. [ABSTRACT FROM AUTHOR]

• New thiazole derivatives were designed based on penicillins to break the resistance against drugs. • The antimicrobial study was achieved against eight bacterial and three fungal strains. • Docking and SAR studies to clarify the allosteric mechanism in antimicrobial activity. The development of resistance against antimicrobial drugs has become a world-wide issue. It is predicted that some or perhaps all the antimicrobial drugs used in clinics will be out of the treatment protocols soon. Therefore, researchers pay more attention to the development of new antimicrobial drugs. For this purpose, we designed and synthesized new 4-methylthiazole-(benz)azole derivatives. The structural elucidation of the compounds was performed by 1H-NMR, 13C-NMR, HSQC, NOESY, HMBC and LC/MS-IT-TOF spectral and elemental analyses. Then, their antimicrobial activity against bacteria and fungi strains was tested. The antibacterial effect of the compounds was found valuable as compared with their anticandidal activity. By combining the findings with molecular docking results, structure-activity relationship (SAR) was explained. Thus, in the development of new antimicrobial agents which can be used as DNA gyrase inhibitors, SAR showed that the products might be used in the discovery of new antimicrobials where their activity is owed to the allosteric effect. Although the effect of compound 3f was modest compared to the reference compound, it was better than the other synthesized compounds. Also, compound 3f has a better allosteric effect and might be a good lead candidate to synthesize new and better active hits. In addition, it was observed that all the synthesized compounds showed half potency against P. aeruginosa compared to the reference drug. On the other hand, no significant difference was seen between compounds against gram-positive or gram-negative bacteria. Briefly, meaningful data to correlate the SAR with thiazole-(benz)azole hybridized compounds were presented in this study. In future projects, the mentioned ideas can be used to synthesize new compounds having better antibacterial activity, particularly against resistant organisms. Compound 3f at allosteric pocket of DNA gyrase (MIC: 15.63-125.00 µg/mL) [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a–3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a–3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system. [ABSTRACT FROM AUTHOR]

• Thirteen novel 1,3,4 triazole-benz/thiazole and hydrazide-thiazole derivatives were synthesized and characterized using spectroscopic techniques. • The final compounds were tested against twelve bacterial species and ten fungal pathogens. • The compounds have shown better antifungal activity compared to antibacterial activity. • Compounds 5c, 5d and 5e were studied in-silico for their proposed interaction with lanosterol 14α-demethylase. • Pharmacokinetics properties of the active compounds were also studied. In this work, thirteen new compounds have been synthesized, characterized and evaluated for their antifungal and antimicrobial activities. Seven of them which contain the thiazole ring were obtained by reacting 2-(2-(2-methoxyphenoxy)propanoyl)- N -phenylhydrazine-1-carbothioamide (3) with phenylacyl bromide derivatives, while the other six compounds that have the 1,2,4-triazole ring (6a-6f) were prepared through couple of steps starting from the same intermediate 2-(2-(2-methoxyphenoxy)acetyl)- N -phenylhydrazine-1-carbothioamide (3). All final compounds were characterized using LC-MS, 1H NMR and 13C NMR spectroscopic techniques. All compounds were tested against twelve bacterial strains and ten fungus species. Derivative (5a) that is N '-(3,4-diphenylthiazol-2(3 H)-ylidene)-2(methoxyphenoxy)propanehydrazide had shown the best activity and selectivity toward Yersinia enterocolitica bacterial type. All compounds demonstrated good activity against filamentous fungi species compared to yeast species. Molecular docking studies also showed that derivatives 2-(2-Methoxyphenoxy)- N '-(4-(4-methoxyphenyl)-3-phenylthiazol-2(3 H)-ylidene)propanehydrazide (5c), N '-(4-(4-chlorophenyl)-3-phenylthiazol-2(3 H)-ylidene)-2-(2-methoxyphenoxy)propanehydrazide (5d) and N -(4-(4-fluorophenyl)-3-phenylthiazol-2(3 H)-ylidene)-2-(2-methoxyphenoxy)propanehydrazide (5e) interacted with the active cavity of lanosterol 14α-demethylase enzyme. [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel derivatives with 1,3,4- oxadiazole as the core ring were synthesized. • Compounds 4f and 4g were the most potent against E. coli bacterial species. • Compounds 4d, 4g, 4h and 4i were the most potent against E. faecalis bacteria. • Compounds 4g, 4i and 4j were the most potent against C. parapsilopsis fungal species. • By using electrochemical studies, compounds 4d, 4f and 4i were able to disrupt dsDNA. The high incidence of antimicrobial-resistant (AMR) infections in recent decades has made the development of novel antimicrobial medications one of the medicinal chemists' top priorities. In this study, synthesis, in vitro antimicrobial activity, electrochemical studies, in silico pharmacokinetic ADME parameters, molecular docking, and molecular dynamic simulations were all performed on several 1,3,4-oxadiazole derivatives. The minimum inhibitory concentrations (MIC) of these compounds were evaluated against eleven species of gram-positive bacteria, gram-negative bacteria and fungal pathogens using azithromycin as the reference antibacterial agent, voriconazole and fluconazole as the reference antifungal agents. Both compounds 4d and 4f were found to be approximately as effective as azithromycin against E. faecalis and E. coli , respectively while three compounds showed antifungal activity against C. parapsilopsis , with MIC values that were identical to fluconazole for 4g and 4i , and to voriconazole for 4j. Also, the most potent derivatives-double stranded DNA (dsDNA) interactions were evaluated using an electrochemical technique. Compounds 4d, 4f and 4i were found to disrupt the structure of dsDNA however compound 4h wasn't able to bind to dsDNA. In addition, the structure-activity relationship (SAR) of compounds 4f and 4d were elucidated by molecular modeling studies. [ABSTRACT FROM AUTHOR]

• New series of oxadiazole and triazole derivatives were synthesized. • The new compounds were tested for their antimicrobial and antioxidative properties. • Compounds 7b showed an interesting antimicrobial activity against B. subtilis only. • Compounds 4a and 7a displayed acceptable antioxidative properties. • Molecular docking and molecular dynamics simulation studies were performed. In the search for new antimicrobial agents, we synthesized a new series of oxadiazole and triazole derivatives. The series of N -(benzothiazol-2-yl)-2-{{5-[(2-chlorophenoxy)methyl]-1,3,4-oxadiazol-2-yl}thio}acetamide (4a-4e) and N -(benzothiazol-2-yl)-2-{{5-[(2-chlorophenoxy)methyl]-4-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl}thio}acetamide (7a-7e) derivatized at the C6 of benzothiazole ring were synthesized and tested for their antimicrobial and antioxidant activity. The compounds were analyzed via 1H NMR, 13C NMR, and HRMS. The pharmacokinetic profile of the targeted compounds was predicted via in silico calculations. None of the tested compounds showed promising antibacterial or antifungal activity in comparison to the used reference agents. Compounds 4a and 7a showed some antioxidant potency in comparison to ascorbic acid but their activity did not match exactly that of ascorbic acid. The binding modes for compounds 4a and 7a were revealed and the optimum poses of the compounds in the active site of the tested oxidant enzyme peroxiredoxin 5 (PRDX5) were displayed via a molecular docking study. Molecular dynamics simulation studies for compound 7a showed the key amino acids in the active site of the enzyme and gave information regarding the mechanism of enzyme interaction. DFT calculations were also made for compounds 4a and 7a. [Display omitted] [ABSTRACT FROM AUTHOR]