Design, Synthesis, and In Vitro and In Vivo Bioactivity Studies of Hydrazide-Hydrazones of 2,4-Dihydroxybenzoic Acid.

In this research, twenty-four hydrazide-hydrazones of 2,4-dihydroxybenzoic acid were designed, synthesized, and subjected to in vitro and in vivo bioactivity studies. The chemical structure of the obtained compounds was confirmed by spectral methods. Antimicrobial activity screening was performed against a panel of microorganisms for all synthesized hydrazide-hydrazones. The performed assays revealed the interesting antibacterial activity of a few substances against Gram-positive bacterial strains including MRSA-Staphylococcus aureus ATCC 43300 (compound 18: 2,4-dihydroxy-N-[(2-hydroxy-3,5-diiodophenyl)methylidene]benzohydrazide-Minimal Inhibitory Concentration, MIC = 3.91 µg/mL). In addition, we performed the in vitro screening of antiproliferative activity and also assessed the acute toxicity of six hydrazide-hydrazones. The following human cancer cell lines were used: 769-P, HepG2, H1563, and LN-229, and the viability of the cells was assessed using the MTT method. The HEK-293 cell line was used as a reference line. The toxicity was tested in vivo on Danio rerio embryos using the Fish Embryo Acute Toxicity (FET) test procedure according to OECD No. 236. The inhibitory concentration values obtained in the in vitro test showed that N-[(4-nitrophenyl)methylidene]-2,4-dihydroxybenzhydrazide (21) inhibited cancer cell proliferation the most, with an extremely low IC50 (Inhibitory Concentration) value, estimated at 0.77 µM for LN-229. In addition, each of the compounds tested was selective against cancer cell lines. The compounds with a nitrophenyl substituent were the most promising in terms of inhibition cancer cell proliferation. The toxicity against zebrafish embryos and larvae was also very low or moderate.

The application of hydrazones and hydrazide-hydrazones in the synthesis of bioactive azetidin-2-one derivatives: A mini review.

The hydrazones and hydrazide-hydrazones beside possessing crucial bioactivity can serve as useful intermediates in the synthesis of heterocyclic systems like 1,3-benzothiazin-4-one, 1,3-thiazolidin-4-one, azetidin-2-one and 1,3,4-oxadiazole derivatives. The azetidin-2-one derivatives show mainly antibacterial, antitubercular and antifungal activity as well as anti-inflammatory, antioxidant, anticonvulsant and antidepressant activity and activity against Parkinson's disease. This review is focused on the literature reports which consider the synthesis and biological properties of azetidin-2-one derivatives.

The N-Substituted-4-Methylbenzenesulphonyl Hydrazone Inhibits Angiogenesis in Zebrafish Tg(fli1: EGFP) Model.

One of the most important therapies of malignant neoplasms, which are the second cause of death worldwide, is focused on the inhibition of pathological angiogenesis within the tumor. Therefore, the searching for the efficacious and relatively inexpensive small-molecule inhibitors of this process is essential. In this research, the anti-angiogenic potential of N-substituted-4-methylbenzenesulphonyl hydrazone, possessing antiproliferative activity against cancer cells, was tested. For this purpose, an intersegmental vessel (ISV) angiogenesis assay was performed using 6 hpf (hours post fertilization), 12 hpf and 24 hpf embryos of zebrafish transgenic strain, Tg(fli1: EGFP). They were incubated with different concentrations of tested molecule and after 24 h the development of intersegmental vessels of the trunk was analysed. In turn, the acute toxicity study in the zebrafish model was mainly conducted on strain AB, using the OECD-approved and recommended fish embryo acute toxicity test (FET) procedure. The results showed the moderate toxicity of N-[(3-chloro-4-methoxyphenyl)methylidene]-4-methylbenzenesulphonohydrazide in above-mentioned model with the LC50 value calculated at 23.04 mg/L. Moreover, newly synthesized molecule demonstrated the anti-angiogenic potential proved in Tg(fli1: EGFP) zebrafish model, which may be promising for the therapy of neoplastic tumors as well as other diseases related to pathological angiogenesis, such as age-related macular degeneration and diabetic retinopathy.

Searching for novel antimicrobial agents among hydrazide-hydrazones of 4-iodosalicylic acid.

Searching for novel antimicrobial agents is up to day topic for many group of researchers due to the fact that each year the number of bacterial strains resistant to currently used medicines increases. Special attention in the scientific literature among various groups of bioactive organic compounds is focused on the antimicrobial activity of hydrazide-hydrazones. Due to this fact presented study is focused on the design, synthesis and in vitro antimicrobial properties of novel hydrazide-hydrazones of 4-iodosalicylic acid. Target compounds were synthesized by the condensation reaction of the hydrazide of 4-iodosalicylic acid with substituted (hetero)aromatic aldehydes. Chemical structure of obtained molecules was confirmed by spectral methods (1H NMR and 13C NMR). Bioactivity screening results revealed interesting antimicrobial properties of tested compounds against reference Gram-positive bacteria and fungi belonging to Candida spp. Especially, hydrazide-hydrazones 3-5 showed very strong or strong bactericidal effect towards some cocci and bacilli (MIC = 7.81-15.62 µg/mL).

The novel adamantane derivatives as potential mediators of inflammation and neural plasticity in diabetes mice with cognitive impairment.

Diabetes is a chronic disease leading to memory difficulties and deterioration of learning abilities. The previous studies showed that modulation of inflammatory pathways in the diabetic brain may reduce dysfunction or cell death in brain areas which are important for control of cognitive function. In the present study, we investigated the neuroprotective actions of newly synthesized adamantane derivatives on diabetes-induced cognitive impairment in mice. Our study relied on the fact that both vildagliptin and saxagliptin belong to DPP4 inhibitors and, contain adamantanyl group. Efficacy of tested compounds at reversing diabetes-induced different types of memory impairment was evaluated with the use of selected behavioural tests. The following neuroinflammatory indicators were also analyzed: neuroinflammatory indicators and the expression of genes involved in the inflammatory response of brain (Cav1, Bdnf). Our study demonstrated that new adamantane derivatives, similarly to DPP4 inhibitors, can restrict diabetes-induced cognitive deficits. We demonstrated that the overexpression of GLP-1-glucagon-like peptide as well as Bdnf, Cav1 genes translate into central blockade of pro-inflammatory synthesis of cytokines and significantly improvement on memory performance in diabetes mice. Newly synthesized adamantane derivatives might have important roles in prevention and treatment of cognitive impairment by inflammatory events in patients with diabetes or related diseases.

Synthesis, Biological Activity and Molecular Docking Studies of Novel Nicotinic Acid Derivatives.

In our research, we used nicotinic acid as a starting compound, which was subjected to a series of condensation reactions with appropriate aldehydes. As a result of these reactions, we were able to obtain a series of twelve acylhydrazones, two of which showed promising activity against Gram-positive bacteria (MIC = 1.95-15.62 µg/mL), especially against Staphylococcus epidermidis ATCC 12228 (MIC = 1.95 µg/mL). Moreover, the activity of compound 13 against the Staphylococcus aureus ATCC 43300 strain, i.e., the MRSA strain, was MIC = 7.81 µg/mL. Then, we subjected the entire series of acylhydrazones to a cyclization reaction in the acetic anhydride, thanks to which we were able to obtain twelve new 3-acetyl-2,5-disubstituted-1,3,4-oxadiazoline derivatives. Obtained 1,3,4-oxadiazolines were also tested for antimicrobial activity. The results showed high activity of compound 25 with a 5-nitrofuran substituent, which was active against all tested strains. The most promising activity of this compound was found against Gram-positive bacteria, in particular against Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538 (MIC = 7.81 µg/mL) and ATCC 43300 MRSA strains (MIC = 15.62 µg/mL). Importantly, the best performing compounds did not show cytotoxicity against normal cell lines. It seems practical to use some of these compounds or their derivatives in the future in the prevention and treatment of infections caused by some pathogenic or opportunistic microorganisms.

Biological Activity, Lipophilicity and Cytotoxicity of Novel 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazolines.

Antibiotic resistance is now a global problem, and the lack of effective antimicrobial agents for the treatment of diseases caused by resistant microbes is increasing. The 3-acetyl-2,5-disubstituted-1,3,4-oxadiazolines presented in this article may provide a good starting point for the development of potential new effective antimicrobial agents useful in the treatment of bacterial and fungal infections. Particular attention is drawn to the 1,3,4-oxadiazole derivative marked with the number 29 with 5-nitrofuran-2-yl substituent in its chemical structure. This substance showed a strong bactericidal effect, especially against Staphylococcus spp., and no cytotoxicity to the L929 normal cell line.

Updated Information on Antimicrobial Activity of Hydrazide-Hydrazones.

Hydrazide-hydrazones possess a wide spectrum of bioactivity, including antibacterial, antitubercular, antifungal, anticancer, anti-inflammatory, anticonvulsant, antidepressant, antiviral, and antiprotozoal properties. This review is focused on the latest scientific reports regarding antibacterial, antimycobacterial, and antifungal activities of hydrazide-hydrazones published between 2017 and 2021. The molecules and their chemical structures presented in this article are the most active derivatives, with discussed activities having a hydrazide-hydrazone moiety as the main scaffold or as a side chain. Presented information constitute a concise summary, which may be used as a practical guide for further design of new molecules with antimicrobial activity.

The bioactivity of benzenesulfonyl hydrazones: A short review.

The synthesis and biological activity evaluation of benzenesulfonyl hydrazones is quite frequently encountered in scientific literature. This class of compounds is very interesting due to the wide spectrum of potential applications in the field of medicinal chemistry. The benzenesulfonyl hydrazones possess mainly antibacterial, antifungal, anticancer, antidepressant properties, activity against Alzheimer's disease, insecticidal activity and ability to inhibit the activity of enzymes. This review is an attempt to gather the literature findings on the most promising bioactive benzenesulfonyl hydrazones.

Novel 2,4,6-Trimethylbenzenesulfonyl Hydrazones with Antibacterial Activity: Synthesis and In Vitro Study.

This research describes the synthesis and in vitro antimicrobial activity study of a series of 2,4,6-trimethylbenzenesulfonyl hydrazones. Twenty-five hydrazones (2-26) were synthesized on the basis of condensation reaction. The in vitro bioactivity study confirmed the potential application of obtained derivatives as antimicrobial agents. Among the tested compounds, the highest activity was discovered for derivative 24, which possessed minimal inhibitory concentration (MIC) ranging from 7.81 to 15.62 µg/mL against Gram-positive reference bacterial strains. Synthesized benzenesulfonyl hydrazones can be applied as potential ligands for the synthesis of bioactive metal complexes.

Novel 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazolines: Synthesis and Biological Activity.

The aim of our study was the two-stage synthesis of 1,3,4-oxadiazole derivatives. The first step was the synthesis of hydrazide-hydrazones from 3-methyl-4-nitrobenzhydrazide and the corresponding substituted aromatic aldehydes. Then, the synthesized hydrazide-hydrazones were cyclized with acetic anhydride to obtain new 3-acetyl-2,3-disubstituted-1,3,4-oxadiazolines. All of obtained compounds were tested in in vitro assays to establish their potential antimicrobial activity and cytotoxicity. Our results indicated that few of the newly synthesized compounds had some antimicrobial activity, mainly compounds 20 and 37 towards all used reference bacterial strains (except Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa) and fungi. These substances showed a strong or powerful bactericidal effect, especially against Staphylococcus spp. belonging to Gram-positive bacteria. Compound 37 was active against Staphylococcus epidermidis at minimal inhibitory concentration (MIC) = 0.48 µg/mL and was characterized by low cytotoxicity. This compound possessed quinolin-4-yl substituent in the second position of 1,3,4-oxadiazole ring and 3-methyl-4-nitrophenyl in position 5. High effectiveness and safety of these derivatives make them promising candidates as antimicrobial agents. Whereas the compound 20 with the 5-iodofurane substituent in position 2 of the 1,3,4-oxadiazole ring showed the greatest activity against S. epidermidis at MIC = 1.95 µg/mL.

New benzenesulphonohydrazide derivatives as potential antitumour agents.

Cancer treatment remains a serious challenge worldwide. Thus, finding novel antitumour agents is of great importance. In the present study, nine new benzenesulphonohydrazide derivatives (1-9) were synthesized, and the chemical structures of the obtained compounds were confirmed by spectral analysis methods, including IR, 1H nuclear magnetic resonance (NMR) and 13C NMR. Experimental lipophilicity values were established using reversed phase-high performance thin layer chromatography. The antiproliferative activity of the synthesized compounds was tested against three tumour cell lines (769-P, HepG2 and NCI-H2170) and one normal cell line (Vero). Among the newly developed molecules, compound 4 exhibited generally the highest cytotoxicity across all tumour cell lines, and it was highly selective. However, higher selectivity towards the tested cancer cell lines was observed using compound 2, when compared with compound 4, which also exhibited significant antiproliferative activity against these tumour cells. In 769-P cells, compounds 5 and 6 were the most selective among all tested compounds. Compound 5 exhibited high cytotoxicity with an estimated IC50 value of 1.94 µM. In the NCI-H2170 cell line, compound 7 was the most cytotoxic and the most selective. In brief, the combination of fluorine and bromine substituents at the phenyl ring showed the most promising results, exerting high cytotoxicity and selectivity towards cancer cells. The renal adenocarcinoma cell line (769-P) appeared to be the most sensitive to the anticancer properties of the novel benzenesulphonohydrazones.

Synthesis and in vitro bioactivity study of new hydrazide-hydrazones of 5-bromo-2-iodobenzoic acid.

In this study 14 novel hydrazide-hydrazones of 5-bromo-2-iodobenzoic acid (3-16) were synthesized on the basis of condensation reaction. The chemical structure of obtained derivatives was established on the basis of spectral data (1H NMR and 13C NMR) and the lipophilicity of synthesized molecules was determined with the use of RP-HPTLC chromatography. Synthesized hydrazide-hydrazones (3-16) were subjected to in vitro cytotoxicity assay and antimicrobial activity analysis against a panel of bacteria and fungi. Among newly synthesized derivatives (3-16), compound 5 was characterized by high, selective and the most diverse cytotoxicity to the cancer cell lines. Molecules 7 and 9 which were substituted with a nitro group in the phenyl ring also exhibited very significant inhibitory effect in the tumor cells and they were very selective. Similarly, compound 13 showed high antiproliferative activity against both cancer cell lines (769-P, HepG2) with satisfactory selectivity. In turn, molecule 8 was characterized by lower inhibitory effect in tumor cells but high selectivity. Derivative 16 proved to be toxic mainly to 769-P cells plausibly by the inhibition of COX-2 mediated signalling pathway. In summary, the introduction of chloro substituent or nitro group to the molecule proved to be most advantageous, providing high cytotoxicity and selectivity to tumor cells. However, the presence of indole scaffold appeared to be responsible for COX-2 inhibitory effect. Some of synthesized hydrazide-hydrazones possessed also moderate antimicrobial activity against a panel of microorganisms.

Synthesis of promising antimicrobial agents: hydrazide-hydrazones of 5-nitrofuran-2-carboxylic acid.

In this research, we synthesized and evaluated for in vitro antimicrobial activity a new series of hydrazide-hydrazones obtained from 5-nitrofuran-2-carboxylic acid. New compounds were identified and characterized by spectral methods (1 H NMR and 13 C NMR). All tested hydrazide-hydrazones proved to be promising antimicrobial agents. Antimicrobial activity and antifungal activity of new derivatives of 5-nitrofuran-2-carboxylic acid were revealed in many cases to be higher than the activity of reference substances (nitrofurantoin, cefuroxime and ampicillin).

Synthesis and Antibacterial Evaluation of Mannich Bases Derived from 1,2,4-Triazole.

The series of novel Mannich bases were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative bacterial strains. The results showed that all compounds were less active than the drugs used as reference, but some of them had moderate potency against Staphylococcus epidermidis ATCC 12228 and Bacillus subtilis ATCC 6633. The presence of a phenyl ring in the position 4 of piperazine seems to be necessary for antibacterial activity in this class of compounds.

Synthesis and in Vitro Antimicrobial Activity Screening of New 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazoline Derivatives.

Thirteen new 3-acetyl-2,5-disubstituted-1,3,4-oxadiazoline derivatives were synthesized from corresponding hydrazide-hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, 1 H-NMR, 13 C-NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4-oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.

Novel functionalized ß-nitrostyrenes: Promising candidates for new antibacterial drugs.

The process of searching for new antibacterial agents is more and more challenging due to the increasing drug resistance which has become a major concern in the field of infection management. Our study presents a synthesis and characterization by IR, UV, 1H NMR and 13C NMR spectra of a homogenous series of 1-EWG functionalized 2-aryl-1-nitroethenes which could prove good candidates for the replacement of traditional antibacterial drugs In vitro screening against a panel of the reference strains of bacteria and fungi and their cytotoxicity towards cultured human HepG2 and HaCaT cells was performed. Antimicrobial results indicated that four of the synthesized compounds exhibited a significant antimicrobial activity against all tested reference bacteria and fungi belonging to yeasts with a specific and strong activity towards B. subtilis ATCC 6633. Two of these compounds had no detectable cytotoxicity towards the cultured human cell lines, making them promising candidates for new antibacterial drugs.

Novel 2,3­disubstituted 1,3­thiazolidin­4­one derivatives as potential antitumor agents in renal cell adenocarcinoma.

Cancer represents one of the main causes of mortality in developed countries. In particular, the overall survival of patients with renal cell carcinoma (RCC) remains poor and the available cytostatic agents are insufficient. Therefore, there is an urgent requirement to identify more effective and safer anticancer drugs. Recently, the evaluation of antitumor activity appeared to be promising for thiazolidinone derivatives. The present study presents the synthesis and the cytotoxicity assays of 1,3­thiazolidin­4­ones. The newly synthesized substances were screened in vitro against selected cancer human renal cell adenocarcinoma cells (769­P), human hepatoblastoma­derived cells (HepG2) and normal green monkey kidney cells (GMK) as a reference cell line. N­[2­(4­methylphenyl)­4­oxo­1,3­thiazolidin­3­yl]acetamide and N­[2­(4­methylphenyl)­4­oxo­1,3­thiazolidin­3­yl]benzamide displayed significant antiproliferative activity towards 769­P. To elucidate the mechanisms of the cytotoxic actions, additional studies on the cell cycle and apoptosis were performed. The aforementioned compounds were responsible for G1 cell cycle arrest and the decrease in cell distribution in the G2 phase in a dose­dependent manner, which prevents mitotic divisions of the 769­P cells. In addition, these novel 2,3­disubstituted 1,3­thiazolidin­4­ones slightly induced apoptosis in 769­P in a dose­dependent manner. It was hypothesized that the 4­methylphenyl group at position 2 of the thiazolidin­4­one scaffold may be regarded as a promising moiety for further development of this group of compounds. Therefore, benzamide moiety appeared to be crucial for triggering cells to apoptotic cell death.

New hydrazide-hydrazones and 1,3-thiazolidin-4-ones with 3-hydroxy-2-naphthoic moiety: Synthesis, in vitro and in vivo studies.

In this research we synthesized, identified and evaluated new hydrazide-hydrazones (1-3) and 1,3-thiazolidin-4-one derivatives (4-6) for in vitro and in vivo activity. New hydrazide-hydrazones (1-3) were obtained by the condensation reaction of 3-hydroxy-2-naphthoic acid hydrazide with appropriate aldehydes. Synthesized hydrazide-hydrazones (1-3) were subjected to cyclization reaction with mercaptoacetic acid which afforded with new 1,3-thiazolidin-4-one derivatives (4-6). Among 1,3-thiazolidin-4-one derivatives tested (4-6), compound 6 exhibited highest and most selective cytotoxicity towards human renal adenocarcinoma cells (769-P) and it did not affect the growth of normal cells (H9c2, GMK). Whereas its hydrazide-hydrazone (compound 3) showed significant antiproliferative activity against both tested human cancer cell lines: renal adenocarcinoma (769-P) and hepatocellular carcinoma (HepG2), however with less selectivity. The in vivo studies focused on the antinociceptive activity of newly synthesized 1,3-thiazolidin-4-one derivatives (4-6). The preliminary screening of novel compounds showed that 1,3-thiazolidin-4-one derivatives (4-6) are safe and not toxic against CNS of mice. Among tested derivatives one compound (6) displayed significant analgesic activity.

Synthesis and in vitro antimicrobial activity screening of new pipemidic acid derivatives.

This article describes the synthesis and antimicrobial activity evaluation of new pipemidic acid derivatives. New compounds were obtained on the basis of Mannich reaction of 4,5-disubstituted 1,2,4-triazole-3-thiones with pipemidic acid. Antimicrobial tests revealed high antibacterial activity of obtained derivatives. Gram-negative rods belonging to Enterobacteriaceae family were particularly most sensitive to new pipemidic acid derivatives. Synthesized compounds exhibited very strong activity towards Proteus mirabilis ATCC 12453, Salmonella typhimurium ATCC 14028 and Escherichia coli ATCC 25922. The minimum inhibitory concentrations of new pipemidic acid derivatives which inhibited the growth of these bacteria were 0.98-7.81 µg/ml, 0.98-7.81 µg/ml and 0.98-3.91 µg/ml, respectively. The antibacterial activity of newly synthesized pipemidic acid derivatives in many cases was far better than the activity of substances used as positive controls (nitrofurantoin, cefuroxime, ampicillin and pipemidic acid).