Structure-activity relationship and cytotoxicity of the new thiosemicarbazide derivatives and their Cu(II) complexes against prostate and melanoma cancer cells.

In this study, eighteen new ligands (B1-B18) containing a thiosemicarbazide core were synthesized and characterized in terms of physicochemical properties, molecular docking and in vitro biological activity. The structures of eleven ligands were investigated using X-Ray diffraction and Hirschfeld Surface analysis. To study the structure-activity relationship, the organic ligands contained pyridin-2-ylmethyl, pyridin-3-ylmethyl or pyridin-4-ylmethyl moieties and various substituents. Their pharmakokinetic profiles and molecular docking results suggest high potential as new drug candidates. The complexing ability of the selected organic ligands was also evaluated, yielding five new Cu(II) complexes (Cu(B1)Cl2, Cu(B4)Cl2, Cu(B10)Cl2, Cu(B17)Cl2, Cu(B18)Cl2). The obtained results suggest the formation of the polymeric structures. All organic ligands and Cu(II) complexes were tested for anticancer activity against prostate and melanoma cancer cells (PC-3, DU-145, LNCaP, A375, G-361, SK-MEL-28) and normal fibroblasts (BJ), as well as antimicrobial activity against six selected bateria strains. Among B1-B18 compounds, B3, B5, B9, B10, B12 and B14 exhibited cytotoxic activity. The studied Cu(II) complexes were in general more active, with Cu(B1)Cl2 exhibiting antincancer activity agains all three prostate cancer cells and Cu(B10)Cl2 reaching the IC50 value equal to 88 µM against G-361 melanoma cells. Several compounds also exhibited antimicrobial activity against gram-positive and gram-negative bacteria. It was found that the type of specific substituents, especially the presence of -chloro and -dichloro substituents had a greated impact on the cytotoxicity than the position of the nitrogen atom in the pyridylacetyl moiety.

New coumarin linked thiazole derivatives as antimycobacterial agents: Design, synthesis, enoyl acyl carrier protein reductase (InhA) inhibition and molecular modeling.

Tuberculosis is a global serious problem that imposes major health, economic and social challenges worldwide. The search for new antitubercular drugs is extremely important which could be achieved via inhibition of different druggable targets. Mycobacterium tuberculosis enoyl acyl carrier protein reductase (InhA) enzyme is essential for the survival of M. tuberculosis. In this investigation, a series of coumarin based thiazole derivatives was synthesized relying on a molecular hybridization approach and was assessed against thewild typeMtb H37Rv and its mutant strain (ΔkatG) via inhibiting InhA enzyme. Among the synthesized derivatives, compounds 2b, 3i and 3j were the most potent against wild type M. tuberculosis with MIC values ranging from 6 to 8 µg/ mL and displayed low cytotoxicity towards mouse fibroblasts at concentrations 8-13 times higher than the MIC values. The three hybrids could also inhibit the growth of ΔkatGmutant strain which is resistant to isoniazid (INH). Compounds 2b and 3j were able to inhibit the growth of mycobacteria inside human macrophages, indicating their ability to penetrate human professional phagocytes. The two derivatives significantly suppress mycobacterial biofilm formation by 10-15 %. The promising target compounds were also assessed for their inhibitory effect against InhA and showed potent effectiveness with IC50 values of 0.737 and 1.494 µM, respectively. Molecular docking studies revealed that the tested compounds occupied the active site of InhA in contact with the NAD+ molecule. The 4-phenylcoumarin aromatic system showed binding interactions within the hydrophobic pocket of the active site. Furthermore, H-bond formation and π -π stacking interactions were also recorded for the promising derivatives.

Cyclization of acyl thiosemicarbazides led to new Helicobacter pylori α-carbonic anhydrase inhibitors.

The eradication of Helicobacter pylori, the etiologic agent of gastric ulcer and adenocarcinoma, is a big concern in clinics due to the increasing drug resistance phenomena and the limited number of efficacious treatment options. The exploitation of the H. pylori carbonic anhydrases (HpCAs) as promising pharmacological targets has been validated by the antibacterial activity of previously reported CA inhibitors due to the role of these enzymes in the bacterium survival in the gastric mucosa. The development of new HpCA inhibitors seems to be on the way to filling the existing antibiotics gap. Due to the recent evidence on the ability of the coumarin scaffold to inhibit microbial α-CAs, a large library of derivatives has been developed by means of a pH-regulated cyclization reaction of coumarin-bearing acyl thiosemicarbazide intermediates. The obtained 1,3,4-thiadiazoles (10-18a,b) and 1,2,4-triazole-3-thiones (19-26a,b) were found to strongly and selectively inhibit HpαCA and computational studies were fundamental to gaining an understanding of the interaction networks governing the enzyme-inhibitor complex. Antibacterial evaluations on H. pylori ATCC 43504 highlighted some compounds that maintained potency on a resistant clinical isolate. Also, their combinations with metronidazole decreased both the minimal inhibitory concentration and minimal bactericidal concentration values of the antibiotic, with no synergistic effect.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

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.

Synthesis and Biological Evaluation of New Compounds with Nitroimidazole Moiety.

Heterocyclic compounds, particularly those containing azole rings, have shown extensive biological activity, including anticancer, antibacterial, and antifungal properties. Among these, the imidazole ring stands out due to its diverse therapeutic potential. In the presented study, we designed and synthesized a series of imidazole derivatives to identify compounds with high biological potential. We focused on two groups: thiosemicarbazide derivatives and hydrazone derivatives. We synthesized these compounds using conventional methods and confirmed their structures via nuclear magnetic resonance spectroscopy (NMR), MS, and elemental analysis, and then assessed their antibacterial and antifungal activities in vitro using the broth microdilution method against Gram-positive and Gram-negative bacteria, as well as Candida spp. strains. Our results showed that thiosemicarbazide derivatives exhibited varied activity against Gram-positive bacteria, with MIC values ranging from 31.25 to 1000 µg/mL. The hydrazone derivatives, however, did not display significant antibacterial activity. These findings suggest that structural modifications can significantly influence the antimicrobial efficacy of imidazole derivatives, highlighting the potential of thiosemicarbazide derivatives as promising candidates for further development in antibacterial therapies. Additionally, the cytotoxic activity against four cancer cell lines was evaluated. Two derivatives of hydrazide-hydrazone showed moderate anticancer activity.

Iron/iron carbide coupled with S, N co-doped porous carbon as effective oxygen reduction reaction catalyst for microbial fuel cells.

As a novel energy device, microbial fuel cells (MFCs) have attracted much attention for their dual functions of electricity generation and sewage treatment. However, the sluggish oxygen reduction reaction (ORR) kinetic on the cathode have hindered the practical application of MFCs. In this work, metallic organic framework derived carbon framework co-doped by Fe, S, N tri-elements was used as alternative electrocatalyst to the conventional Pt/C cathode catalyst in pH-universal electrolytes. The amount of thiosemicarbazide from 0.3 to 3 g determined the surface chemical property, and therefore the ORR activity of FeSNC catalysts. The sulfur/nitrogen doping and Fe/Fe3C embedded in carbon shell was characterized by X-ray photoelectron spectroscopy and transmission electron microscopy. The synergy of iron salt and thiosemicarbazide contributed to the improvement of nitrogen and sulfur doping. Sulfur atoms were successfully doped into the carbon matrix and formed a certain amount of thiophene- and oxidized-sulfur. The optimal FeSNC-3 catalyst synthesized with 1.5 g of thiosemicarbazide exhibited the highest ORR activity with a positive half wave potential of 0.866 V in alkaline and 0.691 V (vs. Reversible Hydrogen Electrode) in neutral electrolyte, which both outperformed the commercial Pt/C catalyst. However, as the amount of thiosemicarbazide surpassed 1.5 g, the catalytic performance of FeSNC-4 was lowered, and this could be assigned to the decreased defects and low specific surface area. The excellent ORR performance in neutral medium urged FeSNC-3 as good cathode catalyst in single chambered MFC (SCMFC). It showed the highest maximum power density of 2126 ± 100 mW m-2, excellent output stability of 8.14% decline in 550 h, chemical oxygen demand removal of 90.7 ± 1.6% and coulombic efficiency of 12.5 ± 1.1%, all superior to those of benchmark SCMFC-Pt/C (1637 ± 35 mW m-2, 15.4%, 88.9 ± 0.9%, and 10.2 ± 1.1%). These outstanding results were associated to the large specific surface area and synergistic interaction of multiple active sites, like Fe/Fe3C, Fe-N4, pyridinic N, graphite N and thiophene-S.

Conjugates of ibuprofen inhibit CHIKV infection and inflammation.

Chikungunya virus infection has become a global health concern because of its high rates of morbidity and mortality in patients with preexisting conditions. Inflammation and arthritis are the major symptoms of CHIKV that persist even after clearance of CHIKV. To develop an antiviral that can reduce infection and manage inflammation independent of the CHIKV infection, ibuprofen (IBU) conjugates with sulfonamide and thiosemicarbazide were synthesized. The conjugates, IBU-SULFA, IBU-ISS and IBU-IBT significantly inhibited CHIKV infection in vitro with a selectivity index (CC50/IC50) of > 11.9, > 25.1 and > 21, respectively. The reduction in infection was attributed to the interference of the conjugates in the early stages of CHIKV life cycle. With no acute oral toxicity, these compounds significantly reduced inflammation and arthritis in rats. Unlike IBU, the conjugates were not ulcerogenic. In conclusion, the conjugation imparted anti-CHIKV properties while retaining the anti-inflammatory properties of IBU. These findings can encourage further validation and research to develop an antiviral for CHIKV to manage both infection and arthritis.

Identification of the first-in-class dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1) with strong anticancer properties.

Molecular docking of a large set of thiosemicarbazide-based ligands resulted in obtaining compounds that inhibited both human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase-1 (IDO1). To the best of our knowledge, these compounds are the first dual inhibitors targeting these two enzymes. As both of them participate in the anticancer response, the effect of the compounds on a panel of cancer cell lines was examined. Among the cell lines tested, lung cancer (A549) and melanoma (A375) cells were the most sensitive to compounds 1 (IC50=0.23 µg/ml), 2 (IC50=0.83 µg/ml) and 3 (IC50=0.25 µg/ml). The observed activity was even 90-fold higher than that of etoposide, with selectivity index values reaching 125. In-silico simulations showed that contact between 1-3 and human DNA topoisomerase II was maintained through aromatic moieties located at limiting edges of ligand molecules and intensive interactions of the thiosemicarbazide core with the DNA fragments present in the catalytic site of the enzyme.

Novel N-methylsulfonyl-indole derivatives: biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardio vascular risks.

Three novel series of N-methylsulfonylindole derivatives 3a&b, 4a-e, and 5a-e were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds 4b, 4e and 5d had selective antibacterial activity against the Gram-negative bacteria, Salmonella enterica and/or E. coli. The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. In vitro anti-inflammatory activity was estimated. Compounds 4d, 4e, 5b, and 5d showed the highest anti-inflammatory activity. The COX-1, COX-2 and 5-LOX inhibitory activities were measured using enzyme immune assay (EIA) kits. Due to the dual COX-2/5-LOX inhibitory activity of compound 5d, its cardiovascular profile was determined by measuring cardiac biomarkers (LDH, CK-MB, and Tn-I). Besides, the histopathological study of the heart muscle and stomach were examined for the most active COX-2 inhibitors 4e and 5d. Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.

Synthesis, characterization, biochemical, and molecular modeling studies of carvacrol-based new thiosemicarbazide and 1,3,4-thiadiazole derivatives.

A series of carvacrol-based thiosemicarbazide (3a-e) and 1,3,4-thiadiazole-2-amine (4a-e) were designed and synthesized for the first time. The structures were characterized by nuclear magnetic resonance and high resolution mass spectroscopy techniques. All compounds were examined for some metabolic enzyme activities. Results indicated that all the synthetic molecules exhibited powerful inhibitory actions against human carbonic anhydrase I and II (hCAI and II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes compared to the standard molecules. Ki values of five novel thiosemicarbazides and five new 1,3,4-thiadiazole-2-amine derivatives (3a-e and 4a-e) for hCA I, hCA II, AChE, and BChE enzymes were obtained in the ranges 0.73-21.60, 0.42-15.08 µM, 3.48-81.48, 92.61-211.40 nM, respectively. After the experimental undertaking, an extensive molecular docking analysis was conducted to scrutinize the intricate details of interactions between the ligand and the enzyme in question. The principal focus of this investigation was to appraise the potency and efficacy of the most active compound. In this context, the calculated docking scores were noted to be remarkably low, with values of -8.65, -7.97, -8.92, and -8.32 kcal/mol being recorded for hCA I, hCA II, AChE, and BChE, respectively. These observations suggest a high affinity and specificity of the studied compounds toward the enzymes, as mentioned earlier, which may pave the way for novel therapeutic interventions aimed at modulating the activity of these enzymes.

Novel ester tethered dihydroartemisinin-3-(oxime/thiosemicarbazide)isatin hybrids as potential anti-breast cancer agents: Synthesis, in vitro cytotoxicity and structure-activity relationship.

A series of ester tethered dihydroartemisinin-3-(oxime/thiosemicarbazide)isatin hybrids 7a-p were designed, synthesized, and assessed for their antiproliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR, and MDA-MB-231/ADR breast cancer cell lines. Among them, hybrids 7a,f (IC50 : 1.33-3.84 µM) showed potent activity against triple-negative (MDA-MB-231 and MDA-MB-231/ADR) breast cancer cell lines, and hybrid 7f (IC50 : 3.90 and 10.18 µM) also demonstrated promising activity against estrogen receptor-positive breast cancer cells (MCF-7 and MCF-7/ADR), and the activity was superior to these of artemisinin, dihydroartemisinin, and ADR, revealing their potential to fight against both drug-sensitive and drug-resistant breast cancers. The enriched structure-activity relationships may facilitate further design of more active candidates.

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.

Retention Behavior of Anticancer Thiosemicarbazides in Biomimetic Chromatographic Systems and In Silico Calculations.

Chromatographic methods, apart from in silico ones, are commonly used rapid techniques for the evaluation of certain properties of biologically active compounds used for their prediction of pharmacokinetic processes. Thiosemicarbazides are compounds possessing anticancer, antimicrobial, and other valuable biological activities. The aim of the investigation was to estimate the lipophilicity of 1-aryl-4-(phenoxy)acetylthiosemicarbazides, to predict their oral adsorption and the assessment of their % plasma-protein binding (%PPB). RP-HPLC chromatographic techniques with five diversified HPLC systems, including columns with surface-bonded octadecylsilanes (C-18), phosphatidylcholine (immobilized artificial membrane, IAM), cholesterol (Chol), and α1-acid glycoprotein (AGP) and human serum albumin (HSA), were applied. The measured lipophilicity of all investigated compounds was within the range recommended for potential drug candidates. However, some derivatives are strongly bonded to HSA (%PPB ≈ 100%), which may limit some pharmacokinetic processes. HPLC determined lipophilicity descriptors were compared with those obtained by various computational approaches.

Promising Schiff bases in antiviral drug design and discovery.

Emerging and re-emerging illnesses will probably present a new hazard of infectious diseases and have fostered the urge to research new antiviral agents. Most of the antiviral agents are analogs of nucleosides and only a few are non-nucleoside antiviral agents. There is quite a less percentage of marketed/clinically approved non-nucleoside antiviral medications. Schiff bases are organic compounds that possess a well-demonstrated profile against cancer, viruses, fungus, and bacteria, as well as in the management of diabetes, chemotherapy-resistant cases, and malarial infections. Schiff bases resemble aldehydes or ketones with an imine/azomethine group instead of a carbonyl ring. Schiff bases have a broad application profile not only in therapeutics/medicine but also in industrial applications. Researchers have synthesized and screened various Schiff base analogs for their antiviral potential. Some of the important heterocyclic compounds like istatin, thiosemicarbazide, quinazoline, quinoyl acetohydrazide, etc. have been used to derive novel Schiff base analogs. Keeping in view the outbreak of viral pandemics and epidemics, this manuscript compiles a review of Schiff base analogs concerning their antiviral properties and structural-activity relationship analysis.

Synthesis and screening of thiosemicarbazide-dithiocarbamate conjugates for antioxidant and anticancer activities.

Thiosemicarbazides (TSCs), dithiocarbamates (DTCs) and their molecular conjugates are promising drug targets. However, hybrids of DTCs with TSCs themselves are rarely investigated. Thus, studies were initiated to synthesize novel system derived from TSC-DTCs to examine their pharmacological applications. The targeted conjugates were designed and synthesized from aryl TSC and aryl DTCs in moderate to good yields. The structures of synthesized compounds were confirmed through FT-IR, 1H NMR, 13C NMR and mass spectrometry. The conjugates have been tested for antioxidant and anticancer activities. The in vitro antioxidant activity was performed using 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging assay, hydrogen peroxide scavenging assay and nitric oxide assay and was also compared with aryl DTCs and aryl TSCs to explore potential of newly synthesized hybrids. The preliminary anticancer screening for cytotoxicity was performed using brine shrimp lethality bioassay using Artemia salina shrimps. Anticancer screening was determined against NCI60 human tumor cell lines at NCI, USA. The results revealed that, newly synthesized hybrids are more active as compared to aryl DTCs and aryl TSCs. Among the tested conjugates for antioxidant screening, 3b was found to be more active than the standard ascorbic acid. The IC50 value of 3b were 8.96 ± 0.089, 10.7 ± 0.016 and 12.29 ± 0.086 µg/ml for DPPH, hydrogen peroxide scavenging assay and nitric oxide assay respectively, whereas IC50 values for standard were 11.75 ± 0.015, 12.03 ± 0.107 and 16.66 ± 0.242 µg/ml respectively. Since hybrids are more active than aryl DTCs and aryl TSCs, only newly synthesized hybrids were screened for anticancer potential. For cytotoxicity screening, compound 3b was found to be most active among synthesized conjugates with LD50 value of 33.86 µg/ml. For anticancer screening, the compounds 3c and 3d were found to be potent among synthesized series with percent growth inhibition of 22 to 44% when screened against colon cancer cell lines whereas, compound 3b showed growth inhibition of 40% for selective leukemia cell line, K-562. The compounds 3b, 3c and 3d with strong electron-withdrawing groups were found to be the most active antioxidant and anticancer agents among the synthesized conjugates.

Design, Synthesis, in Vitro, and in Silico Evaluation of N-Phenylacetamide-Oxindole-Thiosemicarbazide Hybrids as New Potential Tyrosinase Inhibitors.

A novel series of N-phenylacetamide-oxindole-thiosemicarbazide hybrids were synthesized and evaluated for their tyrosinase inhibitory activity. According to tyrosinase inhibition results, all the synthesized compounds showed high tyrosinase inhibitory activity with IC50 values ranging from 0.8 to 3.88 µM in comparison to positive control kojic acid with IC50 value of 36.32 µM. Among tested compounds, analog 7o, containing the 2-methyl-4-nitrophenyl on N-phenylacetamide moiety displayed superior tyrosinase inhibition. This compound was around 45-fold more potent than kojic acid. The kinetic analysis of compound 7o demonstrated that this compound is a competitive inhibitor against tyrosinase. Docking study of this compound demonstrated that compound 7o interacted with critical histidine residues within tyrosinase active site.

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.

Design, Synthesis, Antibacterial Evaluations and In Silico Studies of Novel Thiosemicarbazides and 1,3,4-Thiadiazoles.

The emergence of drug-resistant bacterial strains continues to be one of the major challenges of medicine. For this reason, the importance of searching for novel structures of antibacterial drugs chemically different from the currently known antibiotics is still of great importance. In this study, we synthesized the thiosemicarbazide and 1,3,4-thiadiazole derivatives and tested them for antibacterial activity. In in vitro tests, we examined the activity of the synthesized substances against Gram-positive and Gram-negative bacteria strains. While all 1,3,4-thiadiazoles tested lacked significant activity, the antimicrobial response of the thiosemicarbazides was moderate and it was also dependent on the type and position of the substituent on the phenyl ring. The highest activity towards all Gram-positive bacteria strains was shown by all three linear compounds containing the trifluoromethylphenyl group in the structure. The MIC (minimum inhibitory concentration) values were in the range of 3.9-250 µg/mL. Additionally, we try to explain the mechanism of the antibacterial activity of the tested compounds using the molecular docking to DNA gyrase and topoisomerase IV, following previous reports on the molecular basis of the activity of thiosemicarbazides. Docking simulations allow the purposing dual mechanism of the antibacterial activity of the synthesized compounds through inhibition of topoisomerase IV DNA gyrase with the moderate prevalence of the topoisomerase pathway.

Synthesis and Biological Evaluation of 1-(2-(6-Methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-Substituted Semicarbazides/Thiosemicarbazides as Anti-Tumor Nur77 Modulators.

Nur77 is an orphan nuclear receptor that participates in the occurrence and development of a variety of tumors. Many agonists of Nur77 have been reported to have significant anticancer effects. Our previous studies have found that the introduction of bicyclic aromatic rings, such as naphthalyl and quinoline groups, into the N'-methylene position of indoles' Nur77 modulators can effectively improve the anti-tumor activity of the target compounds. Following our previous studies, a series of novel 1-(2-(6-methoxynaphthalen-2-yl)-6-methylnicotinoyl)-4-substituted semicarbazide/thiosemicarbazide derivatives 9a-9w were designed and synthesized in four steps from 6-methoxy-2-acetonaphthone and N-dimethylformamide dimethylacetal. All compounds were characterized by 1H-NMR, 13C-NMR and HRMS, and their anti-tumor activity on various cancer cell lines such as A549, HepG2, HGC-27, MCF-7 and HeLa are also evaluated. From the series of compounds, 9h exhibited the most potent anti-proliferative activity against several cancer cells. Colony formation and cell cycle experiments showed that compound 9h inhibited cell growth and arrested the cell cycle. Additionally, 9h leads to the cleavage of PARP. We initially explored the mechanism of 9h-induced apoptosis and found that compound 9h can upregulate Nur77 expression and triggered Nur77 nuclear export, indicating the occurrence of Nur77-mediated apoptosis. These results suggested that 9h may be a promising anti-tumor leading compound for the further research.