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A lysosomal targeted fluorescent probe based on coumarin for monitoring hydrazine (N2H4) in living cells was designed and synthesised. The novel fluorescent probe Cou-Lyso-N2H4, in response to N2H4, exhibited good selectivity, low cytotoxicity, and lysosomal localization, which could be suitable for studying the harmfulness of N2H4 in subcellular organelles during various physiological processes.

Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

Drug-induced kidney injury frequently leads to aborted clinical trials and drug withdrawals. Sufficiently sensitive sensors capable of detecting mild signs of chemical insult in cell-based screening assays are critical to identifying and eliminating potential toxins in the preclinical stage. Oxidative stress is a common early manifestation of chemical toxicity, and biomolecule carbonylation is an irreversible repercussion of oxidative stress. Here, we present a novel fluorogenic assay using a sensor, TFCH, that responds to biomolecule carbonylation and efficiently detects modest forms of renal injury with much greater sensitivity than standard assays for nephrotoxins. We demonstrate that this sensor can be deployed in live kidney cells and in renal tissue. Our robust assay may help inform preclinical decisions to recall unsafe drug candidates. The application of this sensor in identifying and analyzing diverse pathologies is envisioned.

Introduction Hydrazines are highly toxic inorganic liquids that are used as propellants in military and aviation industries, such as the U.S. Air Force F-16 Emergency Power Unit and SpaceX SuperDraco Rockets. The most commonly used derivatives include hydrazine, monomethylhydrazine, and 1,1-dimethylhydrazine (unsymmetrical dimethylhydrazine). Industrial workers in close contact with hydrazines during routine maintenance tasks can be exposed to levels well above the National Institute for Occupational Safety and Health relative exposure limits. Materials and Methods A systematic review was performed using PubMed, Web of Science, Google Scholar, National Aeronautics and Space Administration Technical Server, and Defense Technical Information Center, and data related to hydrazine exposures were searched from inception to April 2020. Publications or reports addressing hydrazine toxicity, pathophysiology, and treatment of hydrazine fuel exposure were selected. Results Acute toxic exposures to hydrazine and its derivatives are rare. There are few case reports of acute toxic exposure in humans, and data are largely based on animal studies. The initial search identified 741 articles, manuscripts, and government reports. After screening for eligibility, 51 were included in this review. Eight articles reported acute exposures to hydrazine propellant in humans, and an additional 14 articles reported relevant animal data. Conclusions Exposure to small amounts of hydrazine and its derivatives can cause significant soft tissue injury, pulmonary injury, seizures, coma, and death. Neurologic presentations can vary based on exposure compound and dose. Decontamination is critical as treatment is mainly supportive. High-dose intravenous pyridoxine has been suggested as treatment for hydrazine-related neurologic toxicity, but this recommendation is based on limited human data. Despite recent research efforts to generate less toxic alternatives to hydrazine fuel, it will likely continue to have a role in military and aviation industries. Aerospace and military physicians should be aware of the toxicity associated with hydrazine exposure and be prepared to treat hydrazine toxicity in at-risk populations.

In the present study, using Thorpe's reaction with Gewald's modification, 4-acetylamino-5-acetyl or 5-benzoyl 3-carboxamide compounds 3 or 4 were obtained. From these compounds, two series of compounds (5, 7, and 9 and 6, 8, and 10) were obtained with 98% hydrazine. Compounds 6, 7, 8, and 9 were then reacted with the appropriate aldehydes to afford a series of new isoxazole derivatives (11-18, 27-36, and 37-41) and the main compounds, 19-26 and 42-45, were isoxazolo[4,5-e][1,2,4]triazepine derivatives. The anticarcinogenic activities of selected compounds were tested on six lines of cancer cells, and their activities were compared with the relevant concentrations of the anticarcinogenic drugs cisplatin and doxorubicin in IITD PAN. Several compounds were tested on 60 lines of cancer cells by the NCI (Bethesda, MD, USA). The cyclization of compound 12 into derivative 46 was also carried out. Compound 21 showed extremely high antitumor activity.

Hydrazine has been described as a mutagenic, probable human carcinogen. It is mutagenic in in vitro systems such as bacterial reverse mutation (Ames) tests and some yeast systems, as well as in in vivo systems with drosophila. It was shown to cause chromosome damage both in vitro and in vivo but was negative in some well-validated mammalian mutation systems such as CHO HPRT assays. Importantly, there is only one in vivo gene mutation test reported, which was negative. Our objective was to determine if hydrazine is mutagenic in mammalian test systems. Thus, we conducted an in vitro gene mutation test in Muta™Mouse lung epithelial cells (FE1 cell assay) and a regulatory-compliant in vivo Big Blue® mouse test. Consistent with previous reports, an additional six-well Ames assay showed that hydrazine was mutagenic to bacteria. The FE1 cell assay was negative in conditions with and without metabolic activation when tested to cytotoxicity limits. In the Big Blue® mouse study, female mice received dosages of hydrazine up to 10.9 mg/kg via drinking water for 28 days. This dose is comparable to a dose used in a carcinogenicity study where female mice had significant increases in hepatocellular adenoma at 11.5 mg/kg. There were no increases in mutant frequency in liver and lung, two tissues sensitive to the carcinogenic effects of hydrazine in mice. Our research shows that hydrazine is not mutagenic in mammalian cells either in vitro or in vivo, indicating mutagenicity may not play a role in the carcinogenicity of hydrazine.

A number of new pyrazole and pyrimidine derivatives containing an allylmorpholine fragment were obtained by reactions of chromone-containing allylmorpholines with 1,2- and 1,3-binucleophiles (hydrazine, guanidine, acetamidine). The syntheses were carried out under mild conditions (ethanol, room temperature), and the target products were isolated with high yields. The obtained compounds are of interest as potential cholinesterase inhibitors.

With the widespread use of N2H4, it brings potential risk to human health and environmental safety because of its diverse toxicological functions. In order to determine N2H4 effectively in both env...

Highlights • Monitoring of liver function tests is very important in patient receiving DOT therapy. • There was no significance difference reported in the differential leucocytes count. • We define mechanisms underlying the adverse drug reactions observed following DOTS. • The plasma INH concentration was reported to be high in slow acetylation. • Plasma INH concentration greater than the antimode are slow acetylator., Isoniazid is the most commonly used drug for treatment of tuberculosis, and is administered individually or in combination with other drugs as standard first line therapy. Offsetting its efficacy, severe adverse effects, especially peripheral neuropathy and hepatotoxicity, are associated with isoniazid therapy, limiting its use in tuberculosis. Isoniazid is acetylated in vivo producing hydrazine and acetyl hydrazine, which are responsible for hepatotoxicity. Marked pharmacogenetic differences in acetylation have been reported among different population across the globe. This study evaluates isoniazid acetylation patterns in tuberculosis patients receiving DOT therapy under the Revised National Tuberculosis Control Program (RNTCP) in a specialized tuberculosis hospital in north India. Of 351 patients from whom samples were taken for biochemical analysis of adverse events, 36 were assessed for acetylation patterns. Blood samples were taken 1 h after administration of a 600 mg dose of isoniazid, and plasma concentrations of isoniazid were determined using a validated HPLC method. Of these 36 patients, 20 (55.56%) were slow acetylators and 16 (44.44%) were fast acetylators. Our results are consistent with those of an earlier study conducted in a different region of India. Most biochemical changes produced during long-term isoniazid therapy resolve after therapy is terminated.

Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one‐step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi‐valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one‐step. Next, we performed anchor‐based pharmacophore screening of the libraries and resynthesized top‐ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases., Anchored, yet sailing fast: Here we present the workflow for anchor‐centered docking of tailor‐made virtual libraries and its application to the design, synthesis and biological evaluation of aspartic protease inhibitors. Multi‐component reaction chemistry allows for the rapid synthesis of derivatives, and crystallographic studies show the binding mode of the identified inhibitors.

Abnormal alterations in the expression and biological function of retinoid X receptor alpha (RXRα) have a key role in the development of cancer. Potential modulators of RXRα as anticancer agents are explored in growing numbers of studies. A series of (4/3-(pyrimidin-2-ylamino)benzoyl)hydrazine-1-carboxamide/carbothioamide derivatives are synthesised and evaluated for anticancer activity as RXRα antagonists in this study. Among all synthesised compounds, 6A shows strong antagonist activity (half maximal effective concentration (EC50) = 1.68 ± 0.22 µM), potent anti-proliferative activity against human cancer cell lines HepG2 and A549 cells (50% inhibition of cell viability (IC50) values < 10 µM), and low cytotoxic property in normal cells such as LO2 and MRC-5 cells (IC50 values > 100 µM). Further bioassays indicate that 6A inhibits 9-cis-RA-induced activity in a dose-dependent manner, and selectively binds to RXRα-=LΒD with submicromolar affinity (Kd = 1.20 × 10−7 M). 6A induces time-and dose-dependent cleavage of poly ADP-ribose polymerase, and significantly stimulates caspase-3 activity, leading to RXRα-dependent apoptosis. Finally, molecular docking studies predict the binding modes for RXRα-LBD and 6A., Graphic Abstract Compound 6A with low cytotoxic property in normal cells acts as a selective RXR alpha ligand to promote TNF alpha-mediated apoptosis of cancer cells.

Hydrazine is a well-known genotoxic impurity which may be present in some important drugs, such as isoniazid and hydralazine. It may be ingested along with the drug or generated as a metabolite in the human body. Hence, monitoring the level of hydrazine in the human body is of great importance. A hemicyanine-based NIR fluorescent probe, Hcy-DB, was designed and synthesized for hydrazine detection. This probe exhibited a dramatic off-on NIR fluorescence response toward hydrazine in PBS-DMSO buffer and the detection limit was calculated to be 4.38 ppb. The bioimaging of hydrazine in living H1975 cells was successfully demonstrated. Moreover, the real time imaging of hydrazine, either injected as a foreign agent or generated as a metabolite of isoniazid, was demonstrated in mice and the results clearly disclosed the hydrazine level variation in the liver and kidneys. The injected exogenous hydrazine was mainly distributed in the kidneys and then excreted slowly. After the intragastric administration of isoniazid, hydrazine was quickly generated as a metabolite in the liver and reached a maximum in about 20 min, and then it was excreted slowly through the kidneys. Generally, the investigation provided a promising tool to monitor the level of hydrazine in vivo and thus help to evaluate and control its toxicity more rationally.

Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for μ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands, MACE3 demonstrated a better activity than biphalin after intravenous administration, and its corresponding analogue incorporating the hydrazine linker (MACE2) was able to induce longer lasting analgesia following subcutaneous administration. An analogue of MACE2 containing 2,6-dimethyl-l-tyrosine (MACE4) showed the best potency and in vivo antinociceptive activity of this series.

A series of novel indazole derivatives has been synthesized and evaluated for anticancer, antiangiogenic, and antioxidant activities. The capability of the synthesized compounds 11a–x to hinder the viability of three human cancer cells lines, HEP3BPN 11 (liver), MDA 453 (breast), and HL 60 (leukemia), were assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Among the compounds 11a–x screened, 11c and 11d showed the higher inhibitory activity on the viability of HEP3BPN 11 (liver), when compared with the standard methotrexate. These compounds were further tested to evaluate their potential to inhibit the proangiogenic cytokines associated with tumor development. Compound 11c was found to be a potent antiangiogenic agent against TNFα, VEGF, and EGF, whereas 11d showed potent antiangiogenic activity against TNFα, VEGF, IGF1, TGFb, and leptin inhibition. All the compounds 11a–x were screened for their antioxidant activities using 2,2-diphenyl-1-picryl hydrazine (DPPH), hydroxyl (OH), and superoxide radical (SOR) scavenging activity. Compounds 11n, 11p, 11q, and 11v have shown significant OH radical scavenging activities, also compounds 11c, 11h, and 11k were found to have a DPPH radical scavenging activity and compounds 11a and 11m exhibited better SOR scavenging activity when compared with the reference compound ascorbic acid. In silico molecular docking analysis revealed important structural insights behind observed anti TNFα effect by present indazole compounds.

Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl radical, which was considered to be responsible for its anti-tuberculosis activity. However, it is still not clear whether the previously-proposed N-centered isoniazidyl radical intermediate can be initially produced or not; and if so, what is its exact location on the hydrazine group, distal- or proximal-nitrogen? Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the characteristic and transient N-centered isoniazidyl radical intermediate can be detected and identified from INH activation uniquely by Mn(III)Acetate not by Mn(III) pyrophosphate. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by 15N-isotope-labeling techniques via using 15N-labeled INH. Diisonicotinyl hydrazine was identified as a new reaction product from INH/Mn(III). Analogous results were observed with other hydrazides. This study represents the first detection and unequivocal identification of the initial N-centered isoniazidyl radical and its exact location. These findings should provide a new perspective on the molecular mechanism of INH activation, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.

Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetra hydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.

Hydrazine induced toxicity causes serious harm to the health of humans. The detection of N2H4 in vitro and in vivo has attracted a great deal of attention, especially in the context of fluorescent probes. Although some fluorescent N2H4 probes have been reported, only a few operate in purely aqueous media and, as a result, require the use of organic cosolvents which hinders their use in analysis of real samples. In addition, most of the current N2H4 probes are either "off-on" or "on-off" types, in which it is difficult to eliminate interference from background fluorescence commonly occurring in in vitro and in vivo systems. Furthermore, some probes are unable to differentiate hydrazine from other organic amines. To address the above problems, we developed a novel oligo(ethylene glycol)-functionalized fluorescent probe for the detection of N2H4. The probe, which has a donor-π-acceptor (D-π-A)-type structure, is water-soluble, and it can be utilized to selectively detect N2H4 in both colorimetric and ratiometric mode. Furthermore, the probe is able to differentiate hydrazine from other organic amines and can be used to detect hydrazine vapor and for imaging A549 cells and zebrafish.

A series of Flexible Heteroarotinoid (Flex-Het) analogs was synthesized and their biological activities were evaluated against the A2780 ovarian cancer cell line. The objective of this study was to establish structure-activity relationships (SARs) for new Flex-Het derivatives, which were previously inaccessible due to the limited availability of aryl isothiocyanate precursors. The current work developed a synthesis of isothiocyanate 13 and used it to prepare 14 diverse thiourea analogs of the lead compound SHetA2 (1, NSC-721689) from a range of commercial amines. Additionally, five new ureas were prepared along with nine N-benzylthioureas, five derivatives incorporating hydrazine or hydrazide linkers and four desmethyl compounds. Potencies and efficacies were determined for each derivative. Some of the new Flex-Hets displayed high activity with IC50 values ranging from 1.86 to 4.70 μM and 85.6–95.9% efficacies, which are comparable to or better than the lead compound (IC50 3.17 μM, 84.3% efficacy). Although SHetA2 is scheduled to enter clinical trials in the near future, alternative backup drug candidates have been identified in this work. The new agents possess similar pharmacological properties and retain selective activity against A2780 ovarian cancer cells. Although a mixed SAR was obtained for these analogs, diversified, highly potent molecules were identified for further investigation. In particular, agents 2c-d and 3e-f, which incorporated CF3 and OCF3 groups in place of NO2 on the pendent aryl ring, displayed high activity and excellent differentiation between normal and cancerous cells.

In this research, the new hydrazine-1-carbothioamides (IC32and IC34) having unsubstituted benzimidazole skeleton wereconverted to 1, 2, 4-triazole derivatives (IC42 and IC44) by Ncyclizationreaction using the microwave-assisted synthesismethod in the basic medium with high efficiency in a shorttime. 2-Amino-1,3,4-thiadiazole derivatives (IC52 and IC54)were obtained from the carbothioamides in the acidic mediumby S-cyclization using the conventional method. The structureof all compounds was confirmed by FT-IR, 1HNMR, and 13CNMRspectroscopic techniques. The optimized structures, theoreticalNMR shielding values in DMSO-d6 solvent, the frontier molecularorbital, molecular electrostatic potential, and non-linearoptical properties of these molecules were calculated in theGaussian 09 W package program by using DFT method/B3LYPfunction and 6-311+ +G (d, p) basis set. All calculations exceptNMR calculations were performed in the gas phase and theobtained results were interpreted within the related sections.The discovery of new drugs is of great importance in combatinghealth problems and improving the quality of human life.In the light of this information, molecular docking withAutodock Vina and physicochemical calculations with theSwissADME server were performed at the end of the article.Therefore, the inhibiting potential of the ligands containingdifferent groups in their structure was investigated for the firsttime in this study.

The thiazole derivative N-1-methyl-2-methyl-pyridine)-N-(p-bromophenylthiazol-2-yl)-hydrazine was used to evaluate the acute oral toxicity in Syrian hamsters. The concentration of the doses (300 mg/kg and 2000 mg/kg) were based on the "Class Acute Toxicity Method" displayed in the OECD-423 guide. In addition, renal and liver biochemical tests were performed, as well as histopathological analysis. Our results showed that the compound's lethal dose (LD50) was 1000 mg/kg and classified as category 4 according to the criteria adopted in the experiment's protocol. Biochemical analysis of the liver function's parameters showed that the LD50 values in all animals were higher than the reference values. However, the analyze of the kidney injury parameters showed an increase in the urea's dosage but a decrease in the albumin's dosage in all animals when compared to the reference values. Kidney biochemical analysis also showed that creatinine's level was only higher than the reference values in one animal. Massive damages in the liver were observed, such as hypertrophy and hyperplasia of the hepatocyte, coagulation necrosis, the presence of mononuclear cells in the sinusoidal capillaries, steatosis, cholestasis, and congestion of sinusoidal capillaries and central-lobular veins. The animals presented renal injuries related to congestion of glomerular and interstitial capillaries, nephrosis of contorted proximal and distal tubules and congestion in the medullary region. In conclusion, the thiazole derivative was well tolerated although it caused acute liver and kidney damages. Therefore, these results showed the need of further investigation of this compound in vivo to evaluate the potential therapeutic effects with chronic models.

Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regulating the levels of nucleotides in extracellular environment. However, the pathophysiological functions of these enzymes are not fully understood due to lack of potent and selective NTPDase inhibitors. Herein, a series of oxoindolin hydrazine carbothioamide derivatives is synthesized and screened for NTPDase inhibitory activity. Four compounds were identified as selective inhibitors of h-NTPDase1 having IC50 values in lower micromolar range, these include compounds 8b (IC50 = 0.29 ± 0.02 µM), 8e (IC50 = 0.15 ± 0.009 µM), 8f (IC50 = 0.24 ± 0.01 µM) and 8l (IC50 = 0.30 ± 0.03 µM). Similarly, compound 8k (IC50 = 0.16 ± 0.01 µM) was found to be a selective h-NTPDase2 inhibitor. In case of h-NTPDase3, most potent inhibitors were compounds 8c (IC50 = 0.19 ± 0.02 µM) and 8m (IC50 = 0.38 ± 0.03 µM). Since NTPDase3 has been reported to be associated with the regulation of insulin secretion, we evaluated our synthesized NTPDase3 inhibitors for their ability to stimulate insulin secretion in isolated mice islets. Promising results were obtained showing that compound 8m potently stimulated insulin secretion without affecting the NTPDase3 gene expression. Molecular docking studies of the most potent compounds were also carried out to rationalize binding site interactions. Hence, these compounds are useful tools to study the role of NTPDase3 in insulin secretion.

A hepatocyte-targeting fluorescent N2H4 probe, GHP, was first designed and synthesized employing N-acetylgalactosamine (GalNAc) as the hepatocyte-targeting group and 3-nitrophthalimide as the recognition moiety. The probe can be used to selectively image N2H4 produced by the hydrolysis of isoniazid in HepG2 cells and the liver of zebrafish in situ.

To fight the increasingly worrying bacterial resistance to antibiotics, the discovery and development of new therapeutics is urgently needed. Here, we report on a new series of 1,2,4-triazole-3-thione compounds as inhibitors of metallo-&beta, lactamases (MBLs), which represent major resistance determinants to &beta, lactams, and especially carbapenems, in Gram-negative bacteria. These molecules are stable analogs of 4-amino-1,2,4-triazole-derived Schiff bases, where the hydrazone-like bond has been reduced (hydrazine series) or the 4-amino group has been acylated (hydrazide series), the synthesis and physicochemical properties thereof are described. The inhibitory potency was determined on the most clinically relevant acquired MBLs (IMP-, VIM-, and NDM-types subclass B1 MBLs). When compared with the previously reported hydrazone series, hydrazine but not hydrazide analogs showed similarly potent inhibitory activity on VIM-type enzymes, especially VIM-2 and VIM-4, with Ki values in the micromolar to submicromolar range. One of these showed broad-spectrum inhibition as it also significantly inhibited VIM-1 and NDM-1. Restoration of &beta, lactam activity in microbiological assays was observed for one selected compound. Finally, the binding to the VIM-2 active site was evaluated by isothermal titration calorimetry and a modeling study explored the effect of the linker structure on the mode of binding with this MBL.

Background: The potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge for TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related to cellular oxidation/reduction status and downstream markers of oxidative DNA damage. Methods: We performed intensive pharmacokinetic sampling among isoniazid-treated patients to determine the relative plasma exposures of isoniazid, acetylisoniazid, hydrazine, and acetylhydrazine. Physiologically-based pharmacokinetic modeling was used to estimate liver tissue exposures during a 24-hour dosing interval for each compound. We experimentally treated HepG2 cells with isoniazid and metabolites at equimolar concentrations corresponding to these exposures for 7, 14, and 28 day periods, and performed assays related to redox imbalance and oxidative DNA damage at each timepoint. We related a urine marker of oxidative DNA damage to serum isoniazid pharmacokinetic exposures and pharmacogenetics in a clinical study. Results: Among isoniazid-treated patients, serum concentrations of hydrazine and isoniazid concentrations were highly correlated. At equimolar concentrations that approximated hepatic tissue exposures during a 24-hour dosing interval, hydrazine demonstrated the highest levels of redox imbalance, mitochondrial injury, and oxidative DNA damage over a 28-day treatment period. In a clinical validation study of isoniazid-treated TB patients, peak isoniazid serum concentrations were positively associated with a urine biomarker of oxidative DNA damage. Conclusions: Isoniazid and its metabolites share the potential for oxidative cellular damage, with the greatest effects observed for hydrazine. Future studies should investigate the clinical consequences of oxidative stress with regards to clinical episodes of drug induced liver injury during isoniazid treatment.

Background Application of nanotechnology for crop protection in the form of nanopesticide has attracted significant interest in modern agriculture for the management of devastating polyphagous pests. In the present work, highly stable, ready-to-use water-based nanoformulations of hydrazine-based pesticides were evaluated for their Insect Growth Regulatory potential against the polyphagous insect pest—Spodoptera litura. Also, the nanoformulations were screened for their antifungal behaviour against plant pathogenic fungi; Colletotrichum gloeosporioides, Rhizoctonia solani, Fusarium solani, and Alternaria solani. Results Nanoformulation of sulfonyl acyl hydrazine derivative, NF7, emerged as the best insect growth regulator with GI90 value 0.010 mg L−1 followed by NF4 and NF6 with GI90 0.012 and 0.013 mg L−1, respectively. Results of diet incorporation method showed enhanced efficacy of nanoformulations when compared with topical application method. Antifungal screening showed that many nanoformulations displayed at least 50% growth inhibition for treatment dosage 50–200 mg L−1 against the fungal pathogens tested (C. gloeosporioides, R. solani, F. solani, and A. solani). NF6, NF7, and NF8 were more potent antifungal agents at lower treatment dosages, while at high doses (400 and 800 mg L−1), 100% growth inhibition at concentration was observed against R. solani and F. solani, except NF1 having 64% growth inhibition against F. solani. Conclusion Results presented here are very promising and deliver new nanoformulations of diacyl and sulfonyl acyl hydrazine-based derivatives to be employed as nanopesticide for sustainable crop protection.

BackgroundThe potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge for TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related to cellular oxidation/reduction status and downstream markers of oxidative DNA damage.MethodsWe performed intensive pharmacokinetic sampling among isoniazid-treated patients to determine the relative plasma exposures of isoniazid, acetylisoniazid, hydrazine, and acetylhydrazine. Physiologically-based pharmacokinetic modeling was used to estimate liver tissue exposures during a 24-hour dosing interval for each compound. We experimentally treated HepG2 cells with isoniazid and metabolites at equimolar concentrations corresponding to these exposures for 7, 14, and 28 day periods, and performed assays related to redox imbalance and oxidative DNA damage at each timepoint. We related a urine marker of oxidative DNA damage to serum isoniazid pharmacokinetic exposures and pharmacogenetics in a clinical study.ResultsAmong isoniazid-treated patients, serum concentrations of hydrazine and isoniazid concentrations were highly correlated. At equimolar concentrations that approximated hepatic tissue exposures during a 24-hour dosing interval, hydrazine demonstrated the highest levels of redox imbalance, mitochondrial injury, and oxidative DNA damage over a 28-day treatment period. In a clinical validation study of isoniazid-treated TB patients, peak isoniazid serum concentrations were positively associated with a urine biomarker of oxidative DNA damage.ConclusionsIsoniazid and its metabolites share the potential for oxidative cellular damage, with the greatest effects observed for hydrazine. Future studies should investigate the clinical consequences of oxidative stress with regards to clinical episodes of drug induced liver injury during isoniazid treatment.

In this paper, based on molecular hybridization, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing hydrazine was synthesized and their antiproliferative activities against 5 cancer cell lines (MGC-803, PC3, PC9, EC9706 and SMMC-7721) were evaluated. We found that most of them exhibited obvious growth inhibition effects on these tested cancer cells, especially compound 34 on PC3 cells (IC50 = 26.25 ± 0.28 nM). Meanwhile, compound 34 displayed best selectivity on PC3, compared with the other cancer cell lines, as well as excellent selectivity towards normal cell lines (Het-1A, L02 and GES-1). Further investigations demonstrated that 34 could significantly inhibit PC3 cells’ colony formation, increase cellular ROS content, suppress EGFR expression and induce apoptosis. Our findings indicate that 34 may serve as a novel lead compound for the discovery of more triazolopyrimidine derivatives with improved anticancer potency and selectivity.

Ranunculus muricatus L., an important member of family Ranunculaceae upon submission to phytochemical studies, led to the isolation of a novel natural hydrazine derivative, muricazine (1). Chemical structure of the compound was established with the aid of advanced spectroscopic techniques. It was evaluated for in vitro antioxidant, lipoxygenase, and urease (jack-bean) inhibitory activities. Results suggested that compound 1 could scavenge the DPPH free radical (42.1 ± 0.12 μM) to a great extent as compared to the standard (40.6 ± 0.91 μM). However, it showed moderate inhibitory potential against lipoxygenase (65.2 ± 0.45 μM) and urease (54.8 ± 0.23 μM) enzymes.

Visualizing the in situ release of hydrazine in living systems would give impetus to understand the hydrazine production in the course of drug metabolism in vivo, which is very meaningful but challenging due to the lack of appropriate analytical tools. Here, inspired by the advantages of real-time, non-destructive, and visualization of fluorescence imaging technology, we rationally designed near-infrared cyanine-based fluorescent probe B-CyAS, which possessed outstanding biological compatibility, and a fast response toward (1–100 μM) N2H4 within 7 min. With isoniazid as a model medicine, the dynamic metabolic process of isoniazid to N2H4 in HepG2 cells and zebrafish was successfully in situ visualized, which might provide a promising tool and method for monitoring and evaluating toxic metabolites in biological systems.

A series of quinazoline derivatives with benzylidene hydrazine carboxamide were designed and synthesised as EGFR inhibitors. Most compounds exhibited exceptional anti-proliferative activity against A549, HepG2, MCF-7 and H1975 cells. Furthermore, six compounds demonstrated excellent inhibition activity against EGFRWT with the IC50 value both less than 2 nM. Among the six compounds, 44 exhibited the strongest activity (0.4 nM) and potently inhibited EGFRL858R/T790M (0.1 μM). Excitingly, the most potent compound 14 showed excellent enzyme inhibitory activity with 6.3 nM and 8.4 nM for both EGFRWT and EGFRT790M/L858R. The result of AO single staining and Annexin V/PI staining showed that the compound 14 and 44 could induce remarkable apoptosis of A549 cells. The compound 14 arrested the cell cycle at the S phase and compound 44 arrested the cell cycle at the G0 phase in A549 cells. These preliminary results demonstrate that compound 14 and 44 may be promising lead compound-targeting EGFR.

Since the quinazoline and its derivatives have been considered as a novel class of cancer chemotherapeutic agents that show promising activity against different tumors, a new series of 6-iodo-2-undecylquinazolin-4(3H)-ones were prepared via reaction of 6-iodo-2-undecyl-4H-benzoxazin-4-one with nitrogen nucleophiles, namely, primary amines, 4-amino antipyrine, hydrazine hydrate, diamines, ethanol amine, and/or hydrazide derivatives and screened for their antitumor activity in vitro against a panel of three human tumor cell lines namely; hepatocellular carcinoma (liver) HepG2, colon cancer HCT-116, and mammary gland breast MCF-7. Compounds 14, 16, and 18 showed remarkable broad spectrum antitumor activity. All compounds were fully characterized by means of IR, MS, and 1H-NMR spectra.

Diversity-oriented synthesis of derivatives of natural products is an important approach for the discovery of novel drugs. In this paper, a series of novel 3,4-diaryl-1H-pyrazoles and 3,5-diaryl-1H-pyrazoles derivatives were synthesized through the one-pot reaction of flavones and isoflavones with the hydrazine hydrate and substituted hydrazine hydrate. Some of these novel compounds exhibited antifungal effects against Candida albicans SC5314, and displayed more potent inhibitory activities against the efflux-pump-deficient strain DSY654. In addition, compounds 25, 28 and 32a displayed outstanding reversal activity of azole resistance against clinical azole-resistant Candida albicans in combination with fluconazole (FLC), with FICI values ranging from 0.012 to 0.141. The preliminary structure-activity relationship (SAR) of these compounds was also discussed. In conclusion, this study provides several novel agents that displayed potent antifungal activities alone or together with fluconazole, which makes progress for development of antifungal drugs.

The cytotoxicity of hydrazine (N2H4) is closely associated with mitochondria damages, and real-timely detecting mitochondrial N2H4 is of great importance for the in-depth study of the pathophysiological functions of N2H4 in living system. Although some of N2H4 fluorescent probes have been developed, the selective fluorescence imaging of mitochondrial N2H4 has rarely been reported. Herein, we present a novel mitochondria-targeted fluorescent probe (Rho-N2H4) for imaging N2H4 in living system. In the Rho-N2H4 system, a rhodamine derivative Rho with red emission was employed as the fluorophore, and acetyl group was utilized as response site for hydrazine. Upon treatment with N2H4, Rho-N2H4 displayed a drastically fluorescent signal at 645 nm. With the aid of Rho-N2H4, the fluorescence imaging of mitochondrial N2H4 in living cells was achieved. Assisted by high-definition 3D imaging, Rho-N2H4 can be applied for the imaging of N2H4 in living tissues with a penetration depth of about 50 μm with red emission manner. Furthermore, in vivo experiments demonstrated that Rho-N2H4 can be capable of imaging N2H4 in living animals. We expect that Rho-N2H4 could act as a promising tool for in-depthly unveiling the physiological and pathological roles of mitochondrial N2H4 in living system.

Metabolic pathway disturbances associated with drug-induced liver injury remain unsatisfactorily characterized. Diagnostic biomarkers for hepatotoxicity have been used to minimize drug-induced liver injury and to increase the clinical safety. A metabolomics strategy using rapid-resolution liquid chromatography/tandem mass spectrometry (RRLC-MS/MS) analyses and multivariate statistics was implemented to identify potential biomarkers for hydrazine-induced hepatotoxicity. The global serum and urine metabolomics of 30 hydrazine-treated rats at 24 or 48 h postdosing and 24 healthy rats were characterized by a metabolomics approach. Multivariate statistical data analyses and receiver operating characteristic (ROC) curves were performed to identify the most significantly altered metabolites. The 16 most significant potential biomarkers were identified to be closely related to hydrazine-induced liver injury. The combination of these biomarkers had an area under the curve (AUC) > 0.85, with 100% specificity and sensitivity, respectively. This high-quality classification group included amino acids and their derivatives, glutathione metabolites, vitamins, fatty acids, intermediates of pyrimidine metabolism, and lipids. Additionally, metabolomics pathway analyses confirmed that phenylalanine, tyrosine, and tryptophan biosynthesis as well as tyrosine metabolism had great interactions with hydrazine-induced liver injury in rats. These discriminating metabolites might be useful in understanding the pathogenesis mechanisms of liver injury and provide good prospects for drug-induced liver injury diagnosis clinically.

In this present study, a series of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC50 value of 9.26 ± 1.84 μM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 μM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats.

Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.

New phenolic derivatives bearing hydrazine and 1,3,4-oxadiazole moieties were synthesized and evaluated for their in vitro antimicrobial and antioxidant activities. Most of the compounds revealed pronounced activity against Pseudomonas aeruginosa as well as promising antioxidant activities. N 1-(2,5-Dihydroxybenzoyl)-N 2-(4-methylphenylsulfonyl)hydrazine displayed promising activity against Escherichia coli and P. aeruginosa. N 1-(2,5-Dihydroxybenzoyl)-N 2-(2-naphthalenylmethylene)hydrazine was almost equipotent to the standard antioxidant vitamin C having scavenging activities of 84 and 93%, respectively. In vitro cytotoxicity study revealed that N 1-(2,5-dihydroxybenzoyl)-N 2-(2,3,4-trimethoxyphenylmethylene)hydrazine, N 1-(2,5-dihydroxybenzoyl)-N 2-(3,4,5-trimethoxyphenylmethylene)hydrazine, and N 1-(2,5-dihydroxybenzoyl)-N 2-(4-methylphenylsulfonyl)hydrazine are more safe than reference 5-fluorouracil. In silico drug relevant properties proposed that all compounds have high to moderate drug-likeness scores. Accordingly, these derivatives can be potential leads for development of potent antimicrobial and antioxidant agents.

The HIV-infected patients are co-infected with many bacterial infections in which tuberculosis is most common found worldwide. These patients are often administered with combined therapy of anti-retroviral and anti-tubercular drugs which leads to several complications including hepatotoxicity or adverse drug interactions. The drug-drug interactions between the anti-retroviral and anti-tubercular drugs are not clearly defined and hence, this study was conducted to evaluate the pharmacokinetic drug-drug interactions of Zidovudine (AZT) with Isoniazid (INH) and its hepatotoxic metabolites. Seventy two rats were randomly divided into two major groups with their sub-groups each comprising 6 animals. The Group I received INH alone at a dose of 25 mg/kg; b.w and Group II received AZT (50 mg/kg; b.w) along with INH orally. Pharmacokinetic studies of INH and its metabolites i.e., acetyl hydrazine (ACHY) and hydrazine (HYD) shows that INH and ACHY attains maximum plasma concentration ( Cmax) within 30 minutes and HYD attains Cmax at 1 hour after INH administration and all these analytes disappear from plasma within 4 hours. Pharmacokinetic studies also revealed that AZT treatment did not showed any drug-drug interactions and have no effect on the T1/2, plasma clearance, AUC, Cmax and Tmax of INH and its hepatotoxic metabolites.

Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) they are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells. This article is protected by copyright. All rights reserved.

Lipid peroxidation (LP) is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either initiation or propagation of LP. A more recently explored approach involves scavenging the terminal LP breakdown products that are highly reactive and neurotoxic carbonyl compounds, 4-hydroxynonenal (4-HNE) and acrolein (ACR), to prevent their covalent modification and rendering of cellular proteins nonfunctional leading to loss of ionic homeostasis, mitochondrial failure, and subsequent neuronal death. Phenelzine (PZ) is a U.S. Food and Drug Administration–approved monoamine oxidase (MAO) inhibitor (MAO-I) used for treatment of refractory depression that possesses a hydrazine functional group recently discovered by other investigators to scavenge reactive carbonyls. We hypothesized that PZ will protect mitochondrial function and reduce markers of oxidative damage by scavenging LP-derived aldehydes. In a first set of in vitro studies, we found that exogenous application of 4-HNE or ACR significantly reduced respiratory function and increased markers of oxidative damage (p

Lysyl oxidase has emerged as an important enzyme in cancer metastasis. Its activity has been reported to become upregulated in several types of cancer, and blocking its activity has been shown to limit the metastatic potential of various cancers. The small-molecules phenylhydrazine and β-aminopropionitrile are known to inhibit lysyl oxidase; however, issues of stability, toxicity, and poorly defined mechanisms limit their potential use in medical applications. The experiments presented herein evaluate three other families of hydrazine-derived compounds – hydrazides, alkyl hydrazines, and semicarbazides – as irreversible inhibitors of lysyl oxidase including determining the kinetic parameters and comparing the inhibition selectivities for lysyl oxidase against the topaquinone-containing diamine oxidase from lentil seedlings. The results suggest that the hydrazide group may be a useful core functionality that can be developed into potent and selective inhibitors of lysyl oxidase and eventually find application in cancer metastasis research.

Different 1,3,5-trisubstituted pyrazoline derivatives 2a-c, 3-c, 4a-f, 6a-c, 7a-f and 8a-d were prepared via condensation reaction of the appropriate chalcone 1a-c or 5a-c with various hydrazine derivatives. All compounds were screened for their cytotoxicity against breast MCF-7 cancer cell line and the normal fibroblasts WI-38. Thirteen compounds 2a, 3a, 3c, 4a-d, 6c, 7d, 7e, 8b, 8d and 8f revealed promising cytotoxicity against MCF-7 compared to the reference standard staurosporine and they were safe to the normal fibroblasts WI-38. In addition, compounds 3c, 6c, 7d, 8b and 8d elicited higher cytotoxicity than erlotinib and exhibited promising EGFR inhibitory activity at submicromolar level comparable to that of erlotinib except for compound 8b that may exert its cytotoxicity via another mechanism besides EGFR inhibition. Molecular docking of 3c, 6c, 7d, 8b and 8d in the active site of EGFR confirmed the obtained results.

Hydrazine derivatives are environmental and food pollutants but are also important because of their use in medicine for the treatment of tuberculosis and cancer. However, hydrazines also pose significant health risks to humans as they are mutagenic and carcinogenic. This review examines various metabolic pathways (enzymatic and non-enzymatic) of hydrazines for the formation of reactive species that bind to cellular macromolecules and lead to cellular dysfunction. It is believed that this biotransformation is responsible for the pharmacology and pathophysiology of hydrazine derivatives.

(NRH):quinone oxidoreductase 2 (NQO2) is associated with various processes involved in cancer initiation and progression probably via the production of ROS during quinone metabolism. Thus, there is a need to develop inhibitors of NQO2 that are active in vitro and in vivo. As part of a strategy to achieve this we have used the 4-aminoquinoline backbone as a starting point and synthesized 21 novel analogues. The syntheses utilised p-anisidine with Meldrum's acid and trimethyl orthoacetate or trimethyl orthobenzoate to give the 4-hydrazin-quinoline scaffold, which was derivatised with aldehydes or acid chlorides to give hydrazone or hydrazide analogues, respectively. The hydrazones were the most potent inhibitors of NQO2 in cell free systems, some with low nano-molar IC50 values. Structure-activity analysis highlighted the importance of a small substituent at the 2-position of the 4-aminoquinoline ring, to reduce steric hindrance and improve engagement of the scaffold within the NQO2 active site. Cytotoxicity and NQO2–inhibitory activity in vitro was evaluated using ovarian cancer SKOV-3 and TOV-112 cells (expressing high and low levels of NQO2, respectively). Generally, the hydrazones were more toxic than hydrazide analogues and further, toxicity is unrelated to cellular NQO2 activity. Pharmacological inhibition of NQO2 in cells was measured using the toxicity of CB1954 as a surrogate end-point. Both the hydrazone and hydrazide derivatives are functionally active as inhibitors of NQO2 in the cells, but at different inhibitory potency levels. In particular, 4-((2-(6-methoxy-2-methylquinolin-4-yl)hydrazono)methyl)phenol has the greatest potency of any compound yet evaluated (53 nM), which is 50-fold lower than its toxicity IC50. This compound and some of its analogues could serve as useful pharmacological probes to determine the functional role of NQO2 in cancer development and response to therapy.

The FDA-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anti-cancer chemotherapeutic against a variety of Hh-dependent malignancies. Previously, we performed thorough structure-activity relationship (SAR) studies that defined important functionality and stereochemistry required for ITZ-mediated Hh pathway inhibition. Based off of these results, we have designed, synthesized, and evaluated additional des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. In addition to further probing the ITZ scaffold in terms of anti-Hh activity, these analogues were designed to improve the physicochemical and drug-like properties of the ITZ scaffold. Our studies indicate that the triazolone/side chain region can be replaced with various functionality (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. These results also indicate that while the 2S,4R-cis-dioxolane orientation is preferred for anti-Hh activity, pharmacokinetic studies show that the 2R,4R-trans-dioxolane orientation is favored with regards to metabolism and clearance. Our studies have determined that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. A series of veratric acid derivatives containing benzylidene-hydrazine moieties with different substitutions were synthesized and their inhibitory effect on mushroom tyrosinase and free radical scavenging activity were evaluated. The results indicated that N′-(4-chlorobenzylidene)-3,4-dimethoxybenzohydrazide (D5) and N′-(2,3-dihydroxybenzylidene)-3,4-dimethoxybenzohydrazide (D12) showed the highest tyrosinase inhibitory activity with IC50 values of 19.72 ± 1.84 and 20.63 ± 0.79 μM, respectively, that were comparable with the IC50 value of kojic acid (19.08 ± 1.21 μM). D12 was also a potent radical scavenger with EC50 value of 0.0097 ± 0.0011 mM. The free radical scavenging activity of D12 was comparable with the standard quercetin. The inhibition kinetic analyzed by Lineweaver-Burk plots revealed that compound D5 was a competitive tyrosinase inhibitor. Molecular docking study was carried out for the derivatives demonstrating tyrosinase inhibitory activity. D5 and D12 possessed the most negative estimated free energies of binding in mushroom tyrosinase active site. Therefore, D5 and D12 could be introduced as potent tyrosinase inhibitors that might be promising leads in medicine, cosmetics and food industry.