A potential therapeutic agent for the treatment of hyperuricemia and gout: 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide.

Uric acid, the metabolic product of purines, relies on xanthine oxidase (XOD) for production. XOD is a target for the development of drugs for hyperuricemia (HUA) and gout. Currently, treatment options remain limited for gout patients. 3, 4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a derivative of the natural product protocatechualdehyde with good biological activity. In this work, we identify a DHNB thiosemicarbazide class of compounds that targets XOD. 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazone can effectively inhibit XOD activity (IC50 value: 0.0437 µM) and exhibits a mixed inhibitory effect. In a mouse model of acute hyperuricemia, a moderate dose (10 mg/kg.w) of 3,4-dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide effectively controlled the serum uric acid content and significantly inhibited serum XOD activity. In addition, 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide showed favorable safety profiles, and mice treated with the target compound did not show any symptoms of general toxicity following a single dose of 500 mg/kg. In the allopurinol group, 50 % of the mice died. These results provide a structural framework and mechanism of XOD inhibition that may facilitate the design of hyperuricemia and gout treatments.

The Importance of Substituent Position for Antibacterial Activity in the Group of Thiosemicarbazide Derivatives.

The search for new antibacterial compounds is still a huge challenge for scientists. Each new chemotherapy drug is not 100% effective when introduced into treatment. Bacteria quickly become resistant to known structures. One promising group of new compounds is thiosemicarbazides. In the presented work, we looked for the relationship between structure and antibacterial activity within the group of thiosemicarbazide derivatives. This is a continuation of our previous work. Here, we decided to check to what extent the position of the 3-methoxyphenyl substituent affects potency. We obtained new structures that differ in the positions of the substituent in the thiosemicarbazide skeleton. Based on the obtained results of the biological tests, it can be concluded that the substituent in position 1 of thiosemicarbazide derivatives significantly determines their activity. Generally, among the substituents used, trifluoromethylphenyl turned out to be the most promising. The MIC values for compounds with this substituent are 64 µg/mL towards Staphylococci sp. Using molecular docking, we tried to explain the mechanism behind the antibacterial activity of the tested compounds.

Semicarbazides Carrying Indole Core: Synthesis, Cytotoxicity Evaluation against Human Breast Cancer Cell Lines, and Molecular Modeling Studies.

In this article, we report the synthesis and cytotoxicity evaluation of novel indole-carrying semicarbazide derivatives (IS1-IS15). The target molecules were obtained by the reaction of aryl/alkyl isocyanates with 1H-indole-2-carbohydrazide that was in-house synthesized from 1H-indole-2-carboxylic acid. Following structural characterization by 1 H-NMR, 13 C-NMR, and HR-MS, IS1-IS15 were investigated for their cytotoxic activity against human breast cancer cell lines, MCF-7 and MDA-MB-231. According to the data obtained from the MTT assay, phenyl ring with a lipophilic group at its para-position and alkyl moiety were preferential substituents on the indole-semicarbazide scaffold for antiproliferative activity. The effect of IS12 (N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(1H-indole-2-carbonyl)hydrazine-1-carboxamide), the compound that demonstrated remarkable antiproliferative activity on both cell lines, was also evaluated on the apoptotic pathway. Moreover, the calculation of critical descriptors constituting drug-likeness confirmed the position of the selected compounds in the anticancer drug development process. Finally, molecular docking studies suggested the inhibition of tubulin polymerization as the potential activity mechanism of this class of molecules.

Thiosemicarbazide Derivatives Targeting Human TopoIIα and IDO-1 as Small-Molecule Drug Candidates for Breast Cancer Treatment.

In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identified as dual inhibitors targeting topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1), on two distinct types of breast cancer cells (MCF-7 and MDA-MB-231). The investigated compounds (1-3) selectively suppressed the growth of breast cancer cells and promoted apoptosis via caspase-8- and caspase-9-related pathways. Moreover, these compounds caused S-phase cell cycle arrest and dose-dependently inhibited the activity of ATP-binding cassette transporters (MDR1, MRP1/2 and BCRP) in MCF-7 and MDA-MB-231 cells. Additionally, following incubation with compound 1, an increased number of autophagic cells within both types of the investigated breast cancer cells was observed. During preliminary testing of ADME-Tox properties, the possible hemolytic activities of compounds 1-3 and their effects on specific cytochrome P450 enzymes were evaluated.

Amine oxidase copper-containing 3 aggravates cardiac remodelling by generating hydrogen peroxide after myocardial infarction.

Amine oxidase copper-containing 3 (AOC3) is a member of the semicarbazide-sensitive amine oxidase enzyme family. It acts as an ectoenzyme catalysing the oxidative deamination of primary amines and generating hydrogen peroxide (H2 O2 ). While AOC3 is implicated in cardiovascular diseases such as atherosclerosis, its role in cardiac remodelling after myocardial infarction (MI) is unclear. In this study, we first confirmed a long-term upregulation of AOC3 in both cardiac myofibroblasts after MI in vivo and angiotensin II (ANGII)-treated cardiac fibroblasts in vitro. AOC3 knockdown not only inhibited the activation of cardiac fibroblasts induced by ANGII but also alleviated cardiac fibrosis in mice after MI. Using sh-AOC3 lentiviruses, exogenous recombinant AOC3 (r-AOC3), semicarbazide (an AOC3 inhibitor), and catalase (a hydrogen peroxide scavenger) treatments, we also demonstrated that AOC3 promoted H2 O2 generation, increased oxidative stress, and enhanced ERK1/2 activation, which were responsible for the activation of cardiac fibroblasts. In particular, AOC3 knockdown also improved cardiac function and hypertrophy after MI. Through a coculture system, we confirmed that AOC3 expressed on cardiac myofibroblasts was able to enhance oxidative stress and induce hypertrophy of cardiomyocytes by promoting H2 O2 generation. Similarly, r-AOC3 promoted H2 O2 generation and resulted in oxidative stress and hypertrophy of cardiomyocytes, which were almost inhibited by both semicarbazide and catalase. In conclusion, AOC3 plays a critical role in cardiac fibrosis and hypertrophy after MI by promoting the generation of H2 O2 . AOC3 is a promising therapeutic target against cardiac remodelling. © 2023 The Pathological Society of Great Britain and Ireland.

Evaluation of developmental toxicity in zebrafish embryos and antiproliferative potential against human tumor cell lines of new derivatives containing 4-nitrophenyl group.

The aim of the studies was to evaluate the antiproliferative potential against human tumor cell lines of newly synthetized derivatives containing 4-nitrophenyl group, as well as its impact on developmental toxicity in zebrafish model. We selected 1-(4-nitrobenzoyl)-4-ethylsemicarbazide (APS-1) and 1-[(4-nitrophenyl)acetyl]-4-hexyl-thiosemicarbazide (APS-18) for research. The antiproliferative properties of semicarbazide derivatives were assessed against human cancer cell lines derived from hepatocellular adenocarcinoma (HepG2), renal cell carcinoma (769-P), non-small cell lung cancer (NCI-H1563) and glioblastoma multiforme (LN229) in comparison to the physiological human embryonic kidney (HEK-293) cell line. The influence of the tested substances on the cell cycle and apoptosis was also evaluated. Fish embryo acute toxicity test (FET) was performed based on OECD Guidelines (Test No. 236), and was carried out for the first 5 days post fertilization. The following concentrations of APS-1 and APS-18 were tested: 125-2000 µM and 0.125-1000 µM, respectively. The presented studies on the antiproliferative properties of the new semicarbazide derivatives showed that the compounds APS-1 and APS-18 reduce the viability of human tumor lines. Particularly noteworthy is the strong and selective antiproliferative activity of APS-18 against all neoplastic cell lines, in particular against glioblastoma. Against this tumor line, the compound APS-1 showed an effective inhibitory effect. In the FET we noted that the direct exposure of zebrafish embryos to APS-1 and APS-18 in used range of concentration did not cause morphological abnormalities, including cardiotoxicity. On basis of obtained outcomes it could be concluded that APS-1 and APS-18 may constitute models for further research, design and synthesis of new, safer drugs with more favorable anticancer properties.

Exploring Synthesis and Chemotherapeutic Potential of Thiosemicarbazide Analogs.

BACKGROUND: Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Researchers are continually finding new and more effective medications to battle the diseases. OBJECTIVE: The objective of this study is to identify the emerging role of Thiosemicarbazide analogs for different types of cancer targets with a glance at different novel synthetic routes reported for their synthesis. METHODS: A systematic literature review was conducted from various sources over the last 15 years with the inclusion of published research and review articles that involves the synthesis and use of thiosemicarbazide analogs for different targets of cancer. Data from the literature review for synthesis and anticancer potential for specific targets for cancer studies of thiosemicarbazide analogs are summarized in the paper. RESULTS: There are several emerging studies for new synthetic routes of thiosemicarbazide derivatives with their role in various types of cancers. The main limitation is the lack of clinical trial of the key findings for the emergence of new anticancer medication with thiosemicarbazide moiety. CONCLUSION: Emerging therapies exist for use of a limited number of medications for the treatment of cancer; results of the ongoing studies will provide more robust evidence in the future.

Antitumor Activity and Physicochemical Properties of New Thiosemicarbazide Derivative and Its Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) Complexes.

A novel biologically active thiosemicarbazide derivative ligand L (N-[(phenylcarbamothioyl)amino]pyridine-3-carboxamide) and a series of its five metal(II) complexes, namely: [Co(L)Cl2], [Ni(L)Cl2(H2O)], [Cu(L)Cl2(H2O)], [Zn(L)Cl2] and [Cd(L)Cl2(H2O)] have been synthesized and thoroughly investigated. The physicochemical characterization of the newly obtained compounds has been performed using appropriate analytical techniques, such as 1H and l3C nuclear magnetic resonance (NMR), inductively coupled plasma (ICP), thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR) and magnetic measurements. In order to study the pharmacokinetic profile of the compounds, ADMET analysis was performed. The in vitro studies revealed that the synthesized compounds exhibit potent biological activity against A549 human cancer cell line.

4-Arylthiosemicarbazide Derivatives as Toxoplasmic Aromatic Amino Acid Hydroxylase Inhibitors and Anti-inflammatory Agents.

Approximately one-third of the human population is infected with the intracellular cosmopolitan protozoan Toxoplasma gondii (Tg), and a specific treatment for this parasite is still needed. Additionally, the increasing resistance of Tg to drugs has become a challenge for numerous research centers. The high selectivity of a compound toward the protozoan, along with low cytotoxicity toward the host cells, form the basis for further research, which aims at determining the molecular targets of the active compounds. Thiosemicarbazide derivatives are biologically active organic compounds. Previous studies on the initial preselection of 58 new 4-arylthiosemicarbazide derivatives in terms of their anti-Tg activity and selectivity made it possible to select two promising derivatives for further research. One of the important amino acids involved in the proliferation of Tg and the formation of parasitophorous vacuoles is tyrosine, which is converted by two unique aromatic amino acid hydroxylases to levodopa. Enzymatic studies with two derivatives (R: para-nitro and meta-iodo) and recombinant aromatic amino acid hydroxylase (AAHs) obtained in the E. coli expression system were performed, and the results indicated that toxoplasmic AAHs are a molecular target for 4-arylthiosemicarbazide derivatives. Moreover, the drug affinity responsive target stability assay also confirmed that the selected compounds bind to AAHs. Additionally, the anti-inflammatory activity of these derivatives was tested using THP1-Blue™ NF-κB reporter cells due to the similarity of the thiosemicarbazide scaffold to thiosemicarbazone, both of which are known NF-κB pathway inhibitors.

Does Conjugation of Silver Nanoparticles with Thiosemicarbazide Increase Their Antibacterial Properties?

The opportunistic pathogen, Pseudomonas aeruginosa, uses different mechanisms as well as biofilm production to acquire antibiotic resistance. The polysaccharide synthesis locus (psl) genes play an important role in P. aeruginosa biofilm formation. Therefore, targeting the expression of psl genes can be a suitable strategy to prevent the formation of biofilms by antibiotic-resistant strains. Today, advances in nanotechnology provide a novel potential strategy to combat antibiotic-resistant bacteria. In this study, the silver nanoparticles (Ag NPs) synthesized using a chemical co-precipitation method and, after conjugation with thiosemicarbazide, their effect on the biofilm-forming ability are studied in P. aeruginosa isolates. Chemical properties of synthesized nanoparticles were determined by scanning and transmission electron microscopy, Fourier transform infrared spectroscopy, diffuse reflectance spectroscopy, ultraviolet-visible spectroscopy, X-ray diffraction, and energy dispersive X-ray spectroscopy. The results confirmed the spherical/cubic morphology, solution stability, and good dispersion of Ag@Glu-TSC NPs with an average size of 40-60 nm. In addition, minimum inhibitory concentration values of functionalized Ag NPs were at least twofold lower than the Ag NPs (alone). The quantitative PCR data analysis showed a decrease in the expression of the pslA gene in the presence of Ag@Glu-TSC NPs, up to 60%, which was associated with a reduction of biofilm formation compared to control. In conclusion, the Ag@Glu-TSC NPs can be considered a new inhibitor of biofilm production in antibiotic-resistant bacteria.

Imidazole-Thiosemicarbazide Derivatives as Potent Anti-Mycobacterium tuberculosis Compounds with Antibiofilm Activity.

Mycobacterium tuberculosis (Mtb) is an intracellular pathogenic bacterium and the causative agent of tuberculosis. This disease is one of the most ancient and deadliest bacterial infections, as it poses major health, social and economic challenges at a global level, primarily in low- and middle-income countries. The lack of an effective vaccine, the long and expensive drug therapy, and the rapid spread of drug-resistant strains of Mtb have led to the re-emergence of tuberculosis as a global pandemic. Here, we assessed the in vitro activity of new imidazole-thiosemicarbazide derivatives (ITDs) against Mtb infection and their effects on mycobacterial biofilm formation. Cytotoxicity studies of the new compounds in cell lines and human monocyte-derived macrophages (MDMs) were performed. The anti-Mtb activity of ITDs was evaluated by determining minimal inhibitory concentrations of resazurin, time-kill curves, bacterial intracellular growth and the effect on biofilm formation. Mutation frequency and whole-genome sequencing of mutants that were resistant to ITDs were performed. The antimycobacterial potential of ITDs with the ability to penetrate Mtb-infected human macrophages and significantly inhibit the intracellular growth of tubercle bacilli and suppress Mtb biofilm formation was observed.

Optimized Synthesis of New Thiosemicarbazide Derivatives with Tuberculostatic Activity.

Original results are presented in the field of research that addresses the extension of the reaction of residue of acyl-thiosemicarbazide fixation on the structure of 5-nitrobenzimidazole by a sulphonic group. The aim of the study is the increase of new thiosemicarbazide derivatives' applicative potential in the field of biochemistry, with a wide range of medical applications. The newly obtained compounds were characterized by using elemental analysis and spectral analysis (FT-IR and 1H NMR). A study regarding the optimization of the chemical reactions was made. The performed in vitro biological tests confirmed the tuberculostatic activity of three newly obtained compounds against Mycobacterium tuberculosis.

Schiff base 4-ethyl-1-(pyridin-2-yl) thiosemicarbazide up-regulates the antioxidant status and inhibits the progression of Ehrlich solid tumor in mice.

Cisplatin is an approved cancer therapeutic drug used to treat many solid tumors but its accumulation in the kidney, which causes nephrotoxicity, limits its clinical use. Therefore, investigators seek new alternatives to cisplatin that may be more effective and/or safer. Thiosemicarbazides are of great significance due to their expected biological activity including anticancer activities. The aim of this work is the study of the antitumor effect of Schiff base 4-ethyl-1-(pyridin-2-yl) thiosemicarbazide (HEPTS) on Ehrlich solid tumor-bearing mice in comparison to cancer therapeutic drug cisplatin. The experiment was run using sixty adult female Swiss albino mice. Mice were allocated into six groups (n = 10 mice). Healthy control, EAC control (untreated tumor), EAC + cisplatin, EAC + HEPTS, Healthy + HEPTS, and Healthy + solvent. After scarification, blood samples, liver organs, and solid tumors were collected. Tumor weights and volumes were registered. The concentrations of malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase (CAT), total antioxidant capacity (TAC), nitric oxide (NO), uric acid, creatinine, and urea were assessed. Median survival time (MST) and the percentage increase in lifespan (%ILS) were also calculated. Treatment of tumorized mice with HEPTS significantly reduced both tumor volume and weight while it significantly increased the MST, antioxidant marks and prolonged the %ILS. It also, significantly reduced MAD, creatinine, urea, uric acid, and NO levels. Compared to cisplatin, HEPTS effects were better. Our results recommend HEPTS as one of the probable cisplatin-alternatives for tumor treatment after more validation.

Carboxyl group-modified α-lactalbumin induces TNF-α-mediated apoptosis in leukemia and breast cancer cells through the NOX4/p38 MAPK/PP2A axis.

To clarify the mechanism of semicarbazide-modified α-lactalbumin (SEM-LA)-mediated cytotoxicity, we investigated its effect on human U937 leukemia cells and MCF-7 breast cancer cells in the current study. SEM-LA induced apoptosis in U937 cells, which showed increased NOX4 expression, procaspase-8 degradation, and t-Bid production. FADD depletion inhibited SEM-LA-elicited caspase-8 activation, t-Bid production, and cell death, indicating that SEM-LA activated death receptor-mediated apoptosis in U937 cells. SEM-LA stimulated Ca2+-mediated Akt activation, which in turn increased Sp1- and p300-mediated NOX4 transcription. The upregulation of NOX4 expression promoted ROS-mediated p38 MAPK phosphorylation, leading to protein phosphatase 2A (PP2A)-regulated tristetraprolin (TTP) degradation. Remarkably, TTP downregulation increased the stability of TNF-α mRNA, resulting in the upregulation of TNF-α protein expression. Abolishment of Ca2+-NOX4-ROS axis-mediated p38 MAPK activation attenuated SEM-LA-induced TNF-α upregulation and protected U937 cells from SEM-LA-mediated cytotoxicity. The restoration of TTP expression alleviated the effect of TNF-α upregulation and cell death induced by SEM-LA. Altogether, the data in this study demonstrate that SEM-LA activates TNF-α-mediated apoptosis in U937 cells through the NOX4/p38 MAPK/PP2A axis. We think that a similar pathway can also explain the death of MCF-7 human breast cancer cells after SEM-LA treatment.

4-Arylthiosemicarbazide derivatives as a new class of tyrosinase inhibitors and anti-Toxoplasma gondii agents.

We report herein anti-proliferation effects of 4-arylthiosemicarbazides, with a cyclopentane substitution at N1 position, on highly virulent RH strain of Toxoplasma gondii. Among them, the highest in vitro anti-Toxoplasma activity was found with the meta-iodo derivative. Further experiments demonstrated inhibitory effects of thiosemicarbazides on tyrosinase (Tyr) activity, and good correlation was found between percentage of Tyr inhibition and IC50Tg. To confirm the concept that thiosemicarbazides are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites, the most potent Tyr inhibitors were tested for their efficacy of T. gondii growth inhibition. All of them significantly reduced the number of tachyzoites in the parasitophorous vacuoles (PVs) compared to untreated cells, as well as inhibited tachyzoites growth by impeding cell division. Collectively, these results indicate that compounds with the thiosemicarbazide scaffold are able to disrupt tyrosine metabolism in Toxoplasma tachyzoites by deregulation of their crucial enzyme tyrosine hydroxylase (TyrH).

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 µM and 0.17 µM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 µM for l-tyrosine and 9.30 µM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 µM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.

Thiosemicarbazide Derivatives Decrease the ATPase Activity of Staphylococcus aureus Topoisomerase IV, Inhibit Mycobacterial Growth, and Affect Replication in Mycobacterium smegmatis.

Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide (4) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide (7), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis, as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases.

Synthesis, Characterization and Biological Evaluation of New 3,5-Disubstituted-Pyrazoline Derivatives as Potential Anti-Mycobacterium tuberculosis H37Ra Compounds.

A total of fourteen pyrazoline derivatives were synthesized through cyclo-condensation reactions by chalcone derivatives with different types of semicarbazide. These compounds were characterized by IR, 1D-NMR (1H, 13C and Distortionless Enhancement by Polarization Transfer - DEPT-135) and 2D-NMR (COSY, HSQC and HMBC) as well as mass spectroscopy analysis (HRMS). The synthesized compounds were tested for their antituberculosis activity against Mycobacterium tuberculosis H37Ra in vitro. Based on this activity, compound 4a showed the most potent inhibitory activity, with a minimum inhibitory concentration (MIC) value of 17 µM. In addition, six other synthesized compounds, 5a and 5c-5g, exhibited moderate activity, with MIC ranges between 60 µM to 140 µM. Compound 4a showed good bactericidal activity with a minimum bactericidal concentration (MBC) value of 34 µM against Mycobacterium tuberculosis H37Ra. Molecular docking studies for compound 4a on alpha-sterol demethylase was done to understand and explore ligand-receptor interactions, and to hypothesize potential refinements for the compound.

Synthesis of new 1,2,4-triazole-(thio)semicarbazide hybrid molecules: Their tyrosinase inhibitor activities and molecular docking analysis.

Tyrosinase inhibition is very important in controlling melanin synthesis. If melanin synthesis is not controlled in metabolism, an unwanted increase in melanin synthesis occurs. As melanin plays a role in the formation of skin color, its unusual levels cause some skin disorders such as pregnancy scars, age spots, and especially skin cancer (melanoma). However, the tyrosinase activity is also related to Parkinson's disease and some neurodegenerative diseases. For all these reasons, the medicinal as well as the cosmetic industries focus on research on tyrosinase inhibitors for the treatment of skin disorders and some neurodegenerative diseases. In this study, 32 new 1,2,4-triazole-(thio)semicarbazide hybrid molecules (6a-p and 7a-p) were synthesized, starting from 4-amino-1-pentyl-3-phenyl-1H-1,2,4-triazole-5(4H)-one. These compounds were evaluated for their inhibitory activity against mushroom tyrosinase. The results indicated that 6h, 6m, 6n, and 6p exhibited the most effective inhibitory activity, with IC50 values of 0.00162 ± 0.0109, 0.00166 ± 0.0217, 0.00165 ± 0.019, and 0.00197 ± 0.0063 µM, respectively, compared with kojic acid as the reference drug (IC50 = 14.09 ± 0.02 µM). Also, molecular docking analyses were performed to suggest possible binding poses for the ligands. As a result, derivatives 6h, 6m, 6n, and 6p can be used as promising tyrosinase inhibitor candidates in the medicinal, cosmetics, or food industries.

Thiosemicarbazide binds with the dicopper center in the competitive inhibition of mushroom tyrosinase enzyme: Synthesis and molecular modeling of theophylline analogues.

Theophylline is long known for its anti-ageing and anti-oxidative properties. Moreover, Tyrosinase is a crucial enzyme that regulates the melanin synthetic pathway, which is involved in various physiological metabolic processes including aging. The current paper describes the synthesis of various heterocyclic systems coupled with theophylline moiety along with their tyrosinase inhibition activity in view to identify the potent nucleus. Around 19 compounds were synthesized and screened for enzyme inhibition. Based on the current study, it is suggested that compound 18 having thiosemicarbazide has strong enzyme inhibition potential. The enzyme kinetics and docking studies provide important insights into how the compound interacts with the mushroom tyrosinase active site. The work will provide clue to developing new, potent tyrosinase inhibitors for drug development.