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A series of novel vindoline–piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 μM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 μM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 μM, 10.8 μM, and 6.64 μM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.

Diabetes mellitus is a severe endocrine disease that affects more and more people every year. Modern medical chemistry sets itself the task of finding effective and safe drugs against diabetes. This review provides an overview of potential antidiabetic drugs based on three heterocyclic compounds, namely morpholine, piperazine, and piperidine. Studies have shown that compounds containing their moieties can be quite effective in vitro and in vivo for the treatment of diabetes and its consequences.

Breast cancer is one of the most common malignancies affecting women worldwide, with a significant need for novel therapeutic agents to target specific molecular pathways involved in tumor progression. In this study, a series of rhodanine–piperazine hybrids were designed, synthesized, and evaluated for their anticancer activity, targeting key tyrosine kinases such as VEGFR, EGFR, and HER2. Biological screening against breast cancer cell lines (MCF-7, MDA-MB-231, T47D, and MDA-MB-468) revealed 3 of the 13 tested compounds as the most potent, with 5-(4-[bis(4-fluorophenyl)methyl]piperazin-1-ylmethylidene)-2-thioxo-1,3-thiazolidin-4-one (12) showing the strongest activity, particularly against the MCF-7 and MDA-MB-468 cell lines. Molecular docking studies indicated favorable binding interactions of compound 12 and its 3-phenyl-2-thioxo-1,3-thiazolidin-4-one analogue (15) with HER2, VEGFR, and EGFR, and molecular dynamics simulations further confirmed their stable binding to HER2. These findings highlight the potential of rhodanine–piperazine hybrids as promising leads for developing new anticancer agents targeting breast cancer, particularly HER2-positive subtypes. Further structural optimization could enhance their efficacy and therapeutic profile.

Ten chrysin-based pyrimidine-piperazine hybrids have been evaluated in vitro for antimicrobial activity against eleven bacterial and two fungal strains. All compounds 5a–j exhibited moderate to good inhibition, with MIC values ranging from 6.25 to 250 µg/ml. At 6.25 µg/ml and 12.5 µg/ml MIC values, respectively, compounds 5b and 5h demonstrated the most promising potency against E. coli, outperforming ampicillin, chloramphenicol, and ciprofloxacin. None of the substances had the same level of action as norfloxacin. 5a, 5d, 5g, 5h, and 5i have exhibited superior antifungal efficacy than Griseofulvin against C. albicans with 250 µg/ml MIC. All the compounds were also individually docked into the E. coli DNA gyrase ATP binding site (PDB ID: 1KZN) and CYP51 inhibitor (PDB ID: 5V5Z). The most active compound, 5h and 5g displayed a Glide docking score of − 5.97 kcal/mol and − 10.99 kcal/mol against DNA gyrase and 14α-demethylase enzyme CYP51 respectively. Potent compounds 5b, 5h, and 5g may be used to design new, innovative antimicrobial agents, according to in vitro, ADMET, and in silico biological efficacy analyses.

Antimicrobial resistance poses a critical challenge to global public health, exacerbating morbidity and mortality associated with bacterial infections. This study addresses the urgent need for novel antibacterial agents by exploring the design and synthesis of quinazoline-piperazine phosphorodiamidate hybrids ( 6a-g) as potential DNA gyrase inhibitors. Antibacterial activity was evaluated using the agar well diffusion method, revealing significant inhibition zones for compounds 6f , 6 g , 6a , and 6c compared to the standard drug Amoxyclav. Minimum inhibitory concentration (MIC) measurements further supported the potent antibacterial effects of these compounds. Additionally, compounds 6f , 6 g , and 6a exhibited notable antifungal activity superior to Fluconazole. Molecular docking simulations against DNA gyrase demonstrated strong binding affinities of compounds 6f and 6a with dock scores surpassing that of a standard antibiotic, ciprofloxacin. Detailed analysis of binding interactions highlighted key residues involved in stabilizing the ligand-protein complexes, providing insights into their mechanism of action. Furthermore, in silico ADMET prediction studies revealed that the targeted analogs satisfied the drug like characteristics of CNS acting drugs against antimicrobial diseases.

Advances in medicinal chemistry have led to the development of anticancer and anti-infectious drugs. However, many types of cancer and viral infections such as hepatitis B virus or SARS-CoV-2 are still treated ineffectively. Therefore, further development of effective and selective lead compounds as potential drugs is still highly demanded. In this study, we synthesized a novel series of piperazine-substituted pyranopyridines and evaluated their anticancer and antiviral properties. Antiproliferative activity was determined in a panel of various tumor cell lines as well as non-tumor hepatic HepaRG cells. Mechanisms of cytotoxicity were assessed by fluorescent microscopy techniques. Antiviral activity was analyzed towards DNA and RNA viruses in infectious cell culture systems. Several compounds showed antiproliferative activity towards various cancer cell lines at micromolar and submicromolar concentrations. Mechanisms of cytotoxicity involve the induction of apoptosis and are not mediated via ERK1/2 pathway or oxidative stress. Several compounds exhibit selective activity against hepatitis B virus by preventing the formation of virion particles. This study led to the identification of a novel class of piperazine-substituted pyranopyridines with antiproliferative activity towards a wide range of tumor cell lines as well as the non-toxic inhibitor of HBV virion production.

Background The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA -mutated cancer. This Phase I, open-label, three-part study (Parts A–C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation. Methods PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B. Results A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food ( t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure ( C max ) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC 0–∞ ) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC 0–∞ treatment ratio were within pre-defined bioequivalence limits (0.80–1.25). Adverse event data were consistent with the known safety profile of olaparib. Conclusions Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption.

ObjectiveResveratrol-piperazine cocrystals have been obtained by ultrasound (US) and microwave-assisted (MW) techniques, using the solution and slurry-based methods, to study the influence of the synthesis method on the resulting cocrystal properties, and scalability of the processes. The potential of these cocrystals is represented by the unique properties of their components, resveratrol, and piperazine, which could be also used in veterinary practice. Resveratrol has antimicrobial, antiviral and anticarcinogenic properties, while piperazine can be used in the treatment of parasitic infections.MethodsThe influence of ultrasound and microwave-assisted treatment was studied by varying synthesis parameters such as reaction time, temperature, and US or MW power. The main advantage of using these methods is represented by shorter synthesis time compared to conventional methods, resulting in the direct formation of the cocrystals.ResultsAll samples were obtained in high purity, above 97%. Cocrystal yield correlated positively with ultrasound reaction time, while temperature was not found to influence the microwave synthesis yield up to 50°C, in the case of solution-based methods. MW and US-assisted solution-based methods lead to yields between 52.9 and 68.1%. In the case of the slurry-based method, a minimum reaction time of 5 min leads to the formation of cocrystals with high purity. The resveratrol-piperazine cocrystal's solubility and in vitro antibacterial activity were also evaluated, showing promising results.ConclusionsUltrasound and microwave-assisted techniques offer a viable alternative for synthesizing resveratrol-piperazine cocrystals with short reaction times, high yield, and purity, suitable for scalable resveratrol-piperazine cocrystals.

This study involved the synthesis and characterization of piperazine-citral sulfonyl derivatives 5(a-e) using a variety of spectrum methods, including fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance ( 1 H NMR), carbon-nuclear magnetic resonance ( 13 C NMR), and liquid chromatography mass spectroscopy (LC–MS). To obtain the energy and other quantum chemical computations of all the piperazine-citral sulfonyl derivatives, the following methods were evaluated: density functional theory (DFT); blood brain barrier (BBB); absorption, distribution, metabolism, and excretion (ADME); and prediction of activity spectra of computational screening (PASS) for their potential approaches for biological applications. The synthesized compounds were examined for drug-likeness, total surface area, polar surface area, H-acceptor and H-donor parameters, clogP and clogS, and other physicochemical features. The significant redesign of the piperazine core with the sulfonyl moiety encourages the search for novel antibacterial candidates among the resulting compounds to combat Methicillin-resistant Staphylococcus aureus (MRSA) superbugs. The antibacterial efficacy of 5(a–e) moieties against MRSA was evaluated. The 5c moiety shows a value of 29 µM and 15.08 ± 0.05 zone of inhibition (ZOI) in mm, which is lower than the minimum inhibitory concentration (MIC) value of streptomycin, which is 17 μM (18.16 ± 0.08) ZOI in mm). An in-silico docking study on the protein 3SRW of MRSA confirmed that the biocidal properties were effective against MRSA. The findings that were gathered made it very evident that 5c had a significantly greater docking score, and a stronger binding affinity. To verify the antibacterial activity, SEM, potassium efflux, cellular leakage, and an inhibitory effect on the electron transport chain were employed. HEK 293 cell lines were used to evaluate the 5c analogue’s cytotoxicity, and its behaviour under haemostatic circumstances was well-established. As a prospective antibacterial competitor against MRSA, 5c analogue has the potential to be a cutting-edge medication for the complete eradication of MRSA infections, according to the data obtained.

Multi-target directed ligands (MTDLs) have recently been popularized due to their outstanding efficacy in combating the complicated features of Alzheimer's disease. This study details the synthesis of piperazine-quinoline-based MTDLs through a multicomponent Petasis reaction, targeting multiple factors such as AChE, BuChE, metal chelation to restore metal dyshomeostasis, and antioxidant activity. Some of the synthesized compounds exhibited notable inhibitory activity against AChE and BuChE enzymes at specific concentrations. Among the synthesized compounds compound ( 95 ) containing a 4-chloroaniline moiety and a 4-methoxybenzyl group displayed the most promising inhibitory activities against AChE (IC 50 3.013 µM) and BuChE (IC 50  = 3.144 µM). Compound ( 83 ) featuring 2-methoxyaniline and 4-fluorobenzyl substituents, exhibited the highest BuChE inhibition (IC 50 1.888 µM). Notably, compound ( 79 ) demonstrated 93-times higher selectivity for BuChE over AChE. Molecular docking and molecular dynamics simulations were also performed to explore the binding modes and stability of these compounds with the AChE amd BuChE proteins. Further, kinetics study was performed against AChE for comounds ( 83 and 95 ) which indicated mixed inhibition of the enzyme by these compounds, Amongs the synthesized compounds, nine compounds were assessed for their antioxidant activity, displaying significant antioxidant properties with IC 50 values ranging from 156 µM to 310 µM. Moreover, all the compounds demonstrated metal chelating tendency with Cu +2 , Zn +2 , Fe +2 , Fe +3 and Al +3 . This study provides insights into the design of novel MTDLs, highlighting compound ( 95 ) as a potential candidate for combating Alzheimer's disease. Graphical abstract