Search

Herein, we report the synthesis of a series of new compounds by combining 2-aminobenzothiazole with various profens. The compounds were characterized using techniques such as 1H- and 13C-NMR, FT-IR spectrometry, and high-resolution mass spectrometry (HRMS), with detailed HRMS analysis conducted for each molecule. Their biological activities were tested in vitro, revealing significant anti-inflammatory and antioxidant effects, comparable to those of standard reference compounds. Lipophilicity was experimentally determined through partition coefficient (RM) measurements. To understand their binding affinity, molecular docking studies were perfsormed to analyze interactions with human serum albumin (HSA). The stability of these predicted complexes was further evaluated through molecular dynamics simulations. The results highlight the compounds' promising biological activity and strong affinity for HSA. The new hybrid molecule between 2-ABT and ketoprofen 3b demonstrates significant promise based on the experimental data and is further supported by in silico calculations. Compound 3b exhibits the best hydrogen peroxide scavenging activity among the tested compounds, with an IC50 of 60.24 μg/mL. Furthermore, 3b also displays superior anti-inflammatory activity, with an IC50 of 54.64 μg/mL, making it more effective than the standard ibuprofen (76.05 μg/mL). [ABSTRACT FROM AUTHOR]

Simple Summary: It is of great importance to consider the genotoxicity of drug compounds when designing various compounds with potential biological activity. The synthesis of hybrid molecules comprising natural (5Z,9Z)-diene acids and oleanolic acid was achieved for the first time through the implementation of a novel reaction involving Ti-catalyzed homocyclomagnetization of 1,2-dienes. The synthesized hybrids have been observed to exhibit cytotoxicity against Jurkat, K562, U937, and HEK293 cell lines, and have also demonstrated genotoxicity in Jurkat cells. It seems probable that the principal mechanism of action of these molecules is the inhibition of topoisomerase I, which is of great significance in the context of the potential development of anticancer drugs. Objectives: A series of synthetic analogs of natural (5Z,9Z)-diene acids were synthesized for the first time in the form of hybrid molecules containing an oleanolic acid fragment. This fragment was simultaneously linked by an amide bond to various hetero- and carbocyclic amines and a complex ester bond to (5Z,9Z)-tetradeca-5,9-dienecarboxylic acid, which was synthesized by a new reaction of Ti-catalyzed homocyclomagnification of 1,2-dienes. Results: Among the synthesized hybrids, the highest cytotoxic activity was observed for compound 9a in the series of Jurkat, K562, U937, and HEK293, with IC50 values of 4.5; 3.1; 2.8; and 26.17 μM/L, respectively. Furthermore, the synthesized compound 9a has been observed to induce apoptosis and exhibit genotoxicity in Jurkat culture, which suggests that it may be a promising candidate for further investigation as an antitumor agent. [ABSTRACT FROM AUTHOR]

Objective: Triazole, also known as pyrrdiazole, is a five-membered nitrogen-containing heterocyclic compound composed of two carbon atoms and three nitrogen atoms. Triazole analogs have garnered significant attention due to their extensive applications in medicinal chemistry and their diverse range of biological activities. Methods: With this consideration, we synthesized a diverse library of novel triazolopyridine-based 1,2,3-triazole derivatives (Xa–Xh) by employing Cu alkyne-azide cycloaddition methodology and confirmed the structures by various spectroscopic techniques including mass spectrometry, FT-IR, 1H, and 13C NMR spectroscopy. Further, the synthesized compounds were evaluated for their in silico and in vitro antibacterial potential against various Gram-positive and Gram-negative bacterial strains. Results and Discussion: In the results it is found that compound (Xa) exhibited superior antibacterial activity against S. aureus while compound (Xd) demonstrated comparable activity against E. coli when compared to standard drugs. Molecular docking study also indicated that compounds (Xa) and (Xd) possess the capability to bind to the active sites of S. aureus, E. coli, and P. aeruginosa. Conclusions: All this findings suggested (Xa) and (Xd) as promising alternatives for combating bacterial infections. [ABSTRACT FROM AUTHOR]

The era of chemotherapy began in the 1940s, which is the basis of traditional antitumor approaches and, being one of the most high-tech treatment methods, is still widely used to treat various types of cancer. A promising direction in modern medicinal chemistry is currently the creation of hybrid molecules containing several pharmacophore fragments of different structures. This strategy is successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce side effects. In this work, we synthesized 10 1-aryl derivatives of benzimidazole and benzotriazole and 11 hybrids based on them. Among the compounds obtained, the most promising hybrid molecules were diphenylamines, containing an amino group and a benzotriazole cycle in the ortho position to the bridging NH group, which showed significant cytotoxic activity, excellent antioxidant properties and the ability to suppress the migration activity of tumor cells. Taken together, our results demonstrate that substituted diphenylamine-based bipharmacophoric compounds may serve as a promising platform for further optimization to obtain effective antitumor compounds. [ABSTRACT FROM AUTHOR]

Background/Objectives: To address the unmet clinical needs in the treatment of epilepsy and pain, the continued development of more effective and safer anticonvulsants and analgesics is still necessary. Therefore, herein we report synthesis and antiseizure/antinociceptive evaluation of a focused series of 3-(benzo[b]thiophen-2-yl)pyrrolidine-2,5-dione derivatives. Methods: The anticonvulsant properties were investigated in acute models of seizures, namely the maximal electroshock (MES), the 6 Hz (32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas analgesic activity was tested in the model of a tonic pain/formalin test and oxaliplatin-induced neuropathic pain (in CD-1-mice, i.p.). In addition, a number of in vitro assays were performed, aiming at the evaluation of the drug-like properties of the compounds disclosed herein. Results: We identified 33 as a lead compound with the most promising antiseizure properties, i.e., ED50 (MES) = 27.4 mg/kg and ED50 (6 Hz, 32 mA) = 30.8 mg/kg. Furthermore, 33 at a dose of 100 mg/kg significantly prolonged the latency time to the first seizure episode in the scPTZ model and at high doses did not impaire coordination of mice in the rotarod test (TD50 > 200 mg/kg). Apart from broad antiseizure protection, 33 demonstrated a significant analgesic effect in the formalin test (45 mg/kg, i.p.), and effectively alleviated allodynia in the oxaliplatin-induced neuropathic pain model (30 and 45 mg/kg). The binding assays suggest that the most plausible mechanism of action relies on interaction with the neuronal voltage-sensitive sodium channel (site 2). Furthermore, the drug-like potential of 33 supports favorable in vitro results, i.e., no hepatocytotoxicity and neurocytotoxicity at a high concentration of 100 μM, as well as a lack of mutagenicity at a concentration as high as 500 μM. Conclusions: Compound 33 identified in the current studies is proposed to be an interesting candidate for further preclinical development as therapy for epilepsy and neuropathic pain. [ABSTRACT FROM AUTHOR]

Cancer, a complex group of heterogeneous diseases characterized by the uncontrolled growth and the capability to invade nearby tissues and organs, represents a severe threat to public health worldwide. Over 100 chemotherapeutics have been approved for clinical cancer therapy, but the goal of eradicating cancer remains elusive mainly due to the continuous emergency of drug resistance, necessitating the development of novel anticancer chemotherapeutics. Indoles and carbazoles, contain a benzo[b]pyrrole moiety, are ubiquitous in nature and possess remarkable structural, and anticancer mechanistic diversity, whereas sulfonamides demonstrated potent anticancer efficacy through multiple modes of action, inclusive of apoptosis induction, autophagy regulation, and cell cycle disruption. Accordingly, indole/carbazole and sulfonamide constitute valuable anticancer pharmacophores, and rational hybridization of sulfonamide and indole/carbazole holds a significant functionality in discovery of new anticancer agents. In this review, we summed up the recent advances of sulfonamide-indole/carbazole hybrids with anticancer potential and elucidated the structure-activity relationships as well as mechanisms of action, covering articles published from 2020 onwards, to pave the way for developing more effective anticancer candidates. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most frequent tumors worldwide, based on the number of new cases and deaths. Unfortunately, the low selectivity of action and the rapid development of multiple drug resistances remain the main disadvantages of anticancer compounds. The search for new agents with pronounced antitumor activity is an urgent task in modern biology and medicine. We focused on the investigation of the antitumor potential of novel hybrid pyrrolidinedione–thiazolidinone derivatives. The synthesized derivatives are effective and selective agents that exhibit their antitumor effects in breast carcinoma cells via (1) inhibiting viability, proliferation, and the ability to form colonies; (2) inducing extrinsic and intrinsic apoptotic pathways; and (3) decreasing the level of proteins associated with autophagy, invasion, and metastasis. Our results indicate that synthesized derivatives are potential candidates for deeper exploration of their therapeutic efficiency. The development of new, effective agents for the treatment of breast cancer remains a high-priority task in oncology. A strategy of treatment for this pathology depends significantly on the genotype and phenotype of human breast cancer cells. We aimed to investigate the antitumor activity of new pyrrolidinedione–thiazolidinone hybrid molecules Les-6287, Les-6294, and Les-6328 towards different types of human breast cancer cells of MDA-MB-231, MCF-7, T-47D, and HCC1954 lines and murine breast cancer 4T1 cells by using the MTT, clonogenic and [3H]-Thymidine incorporation assays, flow cytometry, ELISA, and qPCR. The studied hybrids possessed toxicity towards the mentioned tumor cells, with the IC50 ranging from 1.37 to 21.85 µM. Simultaneously, these derivatives showed low toxicity towards the pseudonormal human breast epithelial cells of the MCF-10A line (IC50 > 93.01 µM). Les-6287 at 1 µM fully inhibited the formation of colonies of the MCF-7, MDA-MB-231, and HCC1954 cells, while Les-6294 and Les-6328 did that at 2.5 and 5 µM, respectively. Les-6287 suppressed DNA biosynthesis in the MCF-7, MDA-MB-231, and HCC1954 cells. At the same time, such an effect on the MCF-10A cells was significantly lower. Les-6287 induces apoptosis using extrinsic and intrinsic pathways via a decrease in the mitochondrial membrane potential, increasing the activity of caspases 3/7, 8, 9, and 10 in all immunohistochemically different human breast cancer cells. Les-6287 decreased the concentration of the metastasis- and invasion-related proteins MMP-2, MMP-9, and ICAM-1. It did not induce autophagy in treated cells. In conclusion, the results of our study suggest that the synthesized hybrid pyrrolidinedione–thiazolidinones might be promising agents for treating breast tumors of different types. [ABSTRACT FROM AUTHOR]

In the frame of our diversity-oriented research on multitarget small molecule anticancer agents, utilizing convergent synthetic sequences terminated by Sonogashira coupling reactions, a preliminary selection of representative alkyne-tethered vindoline hybrids was synthesized. The novel hybrids with additional pharmacophoric fragments of well-documented anticancer agents, including FDA-approved tyrosine-kinase inhibitors (imatinib and erlotinib) or ferrocene or chalcone units, were evaluated for their antiproliferative activity on malignant cell lines MDA-MB-231 (triple negative breast cancer), A2780 (ovarian cancer), HeLa (human cervical cancer), and SH-SY5Y (neuroblastoma) as well as on human embryonal lung fibroblast cell line MRC-5, which served as a reference non-malignant cell line for the assessment of the therapeutic window of the tested hybrids. The biological assays identified a trimethoxyphenyl-containing chalcone-vindoline hybrid (36) as a promising lead compound exhibiting submicromolar activity on A2780 cells with a marked therapeutic window. [ABSTRACT FROM AUTHOR]

In this review, we evaluated the biological activities of hybrid molecules incorporating imidazoles—a cornerstone in medicinal chemistry known for their broad pharmacological spectrum, attributed to the chemical characteristics of their nitrogen atoms. In contrast to earlier reviews, which have concentrated their attention only on a single biological activity that is connected with these hybrid molecules, this review brings together the findings of a variety of investigations that cover a wide range of significant activities including antibacterial, antifungal, antituberculosis, antiviral, anticancer, antioxidant, antidiabetic, anti-inflammatory, and analgesic effects, along with the inhibition of cholinesterase, carbonic anhydrase, and monoamine oxidase (MAO) enzymes. Furthermore, we examined significant pharmacophores such as triazole, thiazole, indole, pyrazole, quinoline, sulfonamide, pyridine, chalcone, coumarin, pyrrole, and pyrrolidine, integrated into imidazole hybrids. Molecular docking studies and structure-activity relationship (SAR) discussions provide insight into the interactions of imidazole hybrids with key enzymes and receptors. This work aspires to contribute valuable insights into the development of novel imidazole hybrids, aiming to address critical health challenges of our era. [ABSTRACT FROM AUTHOR]

Amoxicillin and sulbactam are widely used in animal food compounding. Amoxicillin–sulbactam hybrid molecules are bicester compounds made by linking amoxicillin and sulbactam with methylene groups and have good application prospects. However, the residual elimination pattern of these hybrid molecules in animals needs to be explored. In the present study, the amoxicillin–sulbactam hybrid molecule (AS group) and a mixture of amoxicillin and sulbactam (mixture group) were administered to rats by gavage, and the levels of the major metabolites of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and sulbactam were determined by UPLC–MS/MS. The residue elimination patterns of the major metabolites in the liver, kidney, urine, and feces of rats in the AS group and the mixture group were compared. The results showed that the total amount of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and the highest concentration of sulbactam in the liver and kidney samples of the AS group and the mixture group appeared at 1 h after drug withdrawal. Between 1 h and 12 h post discontinuation, the total amount of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine in the two tissues decreased rapidly, and the elimination half-life of the AS group was significantly higher than that in the mixture group (p < 0.05); the residual amount of sulbactam also decreased rapidly, and the elimination half-life was not significantly different (p > 0.05). In 72 h urine samples, the total excretion rates were 60.61 ± 2.13% and 62.62 ± 1.73% in the AS group and mixture group, respectively. The total excretion rates of fecal samples (at 72 h) for the AS group and mixture group were 9.54 ± 0.26% and 10.60 ± 0.24%, respectively. These results showed that the total quantity of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine was eliminated more slowly in the liver and kidney of the AS group than those of the mixture group and that the excretion rate through urine and feces was essentially the same for both groups. The residual elimination pattern of the hybrid molecule in rats determined in this study provides a theoretical basis for the in-depth development and application of hybrid molecules, as well as guidelines for the development of similar drugs. [ABSTRACT FROM AUTHOR]

This study revealed a new inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), a crucial factor in cardiovascular disease and hypertension. The study focuses on the bioactivity compounds that combine adamantane/1,3,4-oxadiazole, potentially inhibiting CaMKIIδ. Various adamantyl-1,3,4-oxadiazole derivatives were synthesized and tested for their efficiency against CaMKIIδ kinase, with 6f being the most potent with an IC50 value of 14.4 μM. Docking studies were carried out to determine the binding processes of these chemicals within the kinase's active region. These discoveries are an important step toward the development of novel treatments for cardiovascular illnesses and hypertension, with the potential for more precise and efficient therapeutic interventions in the future. [ABSTRACT FROM AUTHOR]

Breast cancer, an epithelial malignant tumor that occurs in the terminal ducts of the breast, represents the most prevalent malignancy in women, with over 2 million new diagnoses annually throughout the world. Chemotherapy remains a mainstay in breast cancer therapy, but drug resistance and severe side effects are the major causes for treatment failure. Sulfonamides could act on diverse proteins, enzymes, and receptors and demonstrated promising anti-breast cancer potential. In particular, sulfonamide hybrids have the potential to overcome drug resistance and reduce the side effects since hybrid molecules could act on dual/multiple targets simultaneously. This review focuses on the anti-breast cancer activity, structure-activity relationships, and mechanisms of action of sulfonamide-five-membered heterocycle hybrids, including sulfonamide-azole hybrids, sulfonamide-7-azaindole/indole/oxindole/indoline hybrids, sulfonamide-furan hybrids, and sulfonamide-thiophene hybrids, covering articles published from 2020 to present, to open new avenues for the exploration of novel more effective and multitargeted candidates. [ABSTRACT FROM AUTHOR]

This study focuses on the synthesis of aromatic and heteroaromatic triazole derivatives known for their versatile therapeutic potential in the treatment of cancer, bacterial infections, fungal infections, and malaria. To achieve this, we have developed an efficient synthetic pathway for a wide range of derivatives with a structural motif represented as 2-(4-{[(2-oxo-2H-chromen-4-yl)oxy]methyl}-1H-1,2,3-triazol-1-yl)-N-(4-phenyl-1,3-thiazol-2-yl)acetamide. The structure of the synthesized compounds was determined using 1H and 13C NMR spectroscopy, FT-IR spectroscopy, mass spectrometry, and elemental analysis. Furthermore, this study delves into the antimicrobial and antifungal properties of the coumarin-linked triazole derivatives, highlighting their potential as diverse chemotherapeutic agents with promising clinical applications. Also, the in silico study was performed to assess pharmacokinetics and toxicity profiles. [ABSTRACT FROM AUTHOR]

Cancer, which proliferates and spreads uncontrollably due to the accumulation of genetic and epigenetic factors, is one of the most fatal diseases. Cancer management meets multiple obstacles, and resistance to current therapeutic approaches is the major one. Pyridines/quinolines and sulfonamides can exert the anticancer potential through different mechanisms, and many current available anticancer chemotherapeutics own a pyridine/quinoline or sulfonamide moiety, revealing that pyridine/quinoline and sulfonamide motifs are useful pharmacophores for the discovery of novel anticancer agents. Notably, incorporation of pyridine/quinoline and sulfonamide pharmacophores into one molecule is a promising strategy to overcome drug resistance, improve the activity and reduce the toxicity since pyridine/quinoline-sulfonamide hybrids could simultaneously act on dual/multiple targets in cancer cells. This review outlines the current scenario of pyridine/quinoline-sulfonamide hybrids with the anticancer potential, covering articles published from 2020 onwards, to pave the way for the development of novel more effective and multitargeted anticancer candidates. [ABSTRACT FROM AUTHOR]

For the first time, a synthetic analogue of natural (5Z,9Z)-dienoic acid has been synthesized in the form of a hybrid molecule containing a fragment of oleanolic acid and (5Z,9Z)-tetradeca-5.9-dienedicarboxylic acid, synthesized using a new reaction of Ti-catalyzed homo-cyclomagnesiation 1,2-dienes. The high cytotoxic activity of (5Z,9Z)-14-[(3,28-dioxoolean-12-en-28-yl)oxy]tetradeca-5,9-dienoic acid against tumor cells Jurkat, K562, U937 and HL60 was established. This compound is also an inducer of apoptosis, affects the cell cycle and inhibits human topoisomerase I. [ABSTRACT FROM AUTHOR]

This paper presents an efficient one-pot approach for synthesizing hydroxylated 1,3-dithiane-pyrazolone hybrids. The process involves a reaction between pyrazolone derivatives, carbon disulfide, and epichlorohydrin (ECH). The structures of the produced 1,3-dithian-pyrazolone hybrids are determined based on their IR, 1H NMR, 13C NMR, and Mass spectroscopic data. Analysis of the 1H NMR spectra of compounds 4b and 4d revealed first-order splitting of the methylene hydrogens of the 1,3-dithian moiety, indicating that the OH group occupies an axial position in the preferred conformation of these derivatives. Despite the use of optically pure ECH as a starting material, racemization of products occurs during the reaction. The proposed reaction mechanism provides a rational explanation for this observation. [ABSTRACT FROM AUTHOR]

Twelve dihydroartemisinin-chloro/bromoisatin hybrids were synthesized by combining dihydroartemisinin with chloro/bromoisatin and their in vitro anti-proliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR, and MDA-MB-231/ADR breast cancer cell lines was evaluated. A significant part of the synthesized hybrids exhibited significant anti-breast cancer activity against the tested cell lines and showed potential in overcoming drug resistance. 2-{4-Bromo-2-oxo-1-[4-({(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl}oxy)butyl]indolin-3-ylidene}hydrazine-1-carbothioamide was found to be the most potent among all the synthesized hybrids, with IC50 values of 28.6–39.4 µM against the four breast cancer cell lines, and the activity was more than 2.53 times greater than that of adriamycin (IC50 >100 µM) against multidrug-resistant MCF-7/ADR and MDA-MB-231/ADR cancer cell lines. A preliminary structure-activity relationships (SARs) analysis indicated that chloro/bromo substitution at the C6 position of the isatin moiety was more favorable than at the C4 position; the substituents at the C3 position of the isatin moiety and the carbon spacers between DHA and isatin moieties appeared to play a more significant role. The enriched SARs obtained from this study may provide useful information for the rational design of dihydroartemisinin-isatin hybrids with improved anti-breast cancer activity and drug resistance overcoming capabilities. [ABSTRACT FROM AUTHOR]

Bacterial infections are a global issue, causing sickness and death, mainly in developing nations. Resistance to current medicines is a significant issue in healthcare. Overcoming the resistance problem will necessitate the development of molecules with novel modes of action that do not cross-react with existing medicines. Synthesis of new bis-heterocycles linked to the piperazine core and vanillin unit is disclosed in this regard. The target compounds were produced via the reaction of 4,4′-((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(oxy))bis(3-methoxybenzaldehyde) with various reagents using the Hantzsch, Biginelli, and Michael’s reactions. All the generated compounds were tested for their antibacterial activity against a variety of bacterial strains. The antibacterial activity evaluations revealed that compound 32 has the most promising activity against Pseudomonas aeruginosa (19.5 ± 0.7 mm) compared to Ofloxacin (17 mm) with minimum inhibitory concentration (MIC) equaled to 625 µg/mL. A molecular docking investigation revealed that compound 32 had the greatest binding affinity for bacterial enoyl reductase (−36.13 ± 0.2 Kcal/mole) when compared to the co-crystallized ligand (−16.8 ± 0 Kcal/mole).

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form of cell death plays a significant role in the multifaceted AD pathogenesis through generation of reactive oxygen species (ROS), mitochondrial damage, lipid peroxidation, and reduction in glutathione peroxidase 4 (GPX4) enzyme activity and levels. Aberrant liquid-liquid phase separation (LLPS) of tau drives the growth and maturation of NFTs contributing to AD pathogenesis. In this study, we strategically combined the structural and functional properties of gallic acid (GA) and cyclic dipeptides (CDPs) to synthesize hybrid molecules that effectively target both ferroptosis and amyloid toxicity in AD. This innovative approach marks a paradigm shift from conventional therapeutic strategies. This is the first report of a synthetic small molecule (GCTR) that effectively combats ferroptosis, simultaneously restoring enzymatic activity and enhancing cellular levels of its master regulator, GPX4. Further, GCTR disrupts Fe3+-induced LLPS of tau, and aids in attenuation of abnormal tau fibrillization. The synergistic action of GCTR in combating both ferroptosis and amyloid toxicity, bolstered by GPX4 enhancement and modulation of Fe3+-induced tau LLPS, holds promise for the development of small molecule-based novel therapeutics for AD.

Hybrid molecules can be defined as chemical entities with two or more structural domains, namely pharmacophores, having a specific biological effect. In many cases, when at least one of the components is biologically inactive, it is rather correct to call them "derivatives", despite the fact that in the literature they are often mentioned also as hybrids. We have summarized such types of molecules, in which one of the components is mostly a real pharmacophore, i.e., flavone, which is one of the best-known natural bioactive substances. Structures, synthetic methods, medicinal indications, and more important activity data are presented. [ABSTRACT FROM AUTHOR]

In this study, a one-pot reaction between β-keto esters or dialkyl acetylenedicarboxylates with hydrazines, carbon disulfide, and dialkyl acetylenedicarboxylates in the presence of triethylamine is reported. This reaction proceeded at room temperature and was completed within 6 h to produce functionalized pyrazolone-1,4-dithiafulvene hybrids in good yields. [ABSTRACT FROM AUTHOR]

In this study, we designed and synthesized some new ciprofloxacin‐benzimidazole hybrid compounds and evaluated them for their antimicrobial activity against four Gram‐positive (B. subtilis, B. megaterium, E. faecalis and S. aureus) and five Gram‐negative (E. coli, E. cloacae, P. aeruginosa, S. typhimurium and Y. pseudotuberculosis) bacteria. Most of the synthesized compounds were found to show better or equivalent activities when compared with the standard drug ciprofloxacin. Among the tested compounds, compounds 4 v and 4 w showed more or the same activities against most of the bacteria. In the light of the information obtained from this study, the results showed that the synthesized hybrid compounds could be potential antibiotic agents. Antimicrobial activities were also confirmed by molecular docking studies against active site of Staphylococcus aureus DNA gyrase. Based on docking results, the compound 4e‐protein complex having the best score was used to perform 100 ns MD simulations to analyze the dynamic behavior and stability of the complex. Furthermore, the active compounds demonstrated acceptable ranges of ADMET properties such as partition coefficients, cellular permeability, and toxicity values. [ABSTRACT FROM AUTHOR]

Combining compounds with complementary bioactivities to create hybrid molecules is a new idea in drug research. In this work, we created novel hybrid molecules including bis-heterocycles connected by an isopropanol unit. This is accomplished by the condensation of 4,4'-((2-hydroxypropane-1,3-diyl)bis(oxy))dibenzaldehyde with the appropriate reagents using Hantzsch, Michael, and Biginelli reactions. The structures of the newly synthesized compounds are determined by elemental analysis, 1H NMR, 13C NMR, IR, and MS spectra. [ABSTRACT FROM AUTHOR]

This article presents two new series of tetrazole and morpholine hybrid derivatives that were produced using simple processes and good yields from 2-difluoro-4-nitrobenzene, morpholine, acid chlorides/(or) aryl iodide. By using IR, NMR, and HRMS spectrometry, all compounds were identified. The synthesized compounds were tested for anticancer efficacy against histiocytic lymphoma (U-937) cells. The route of action was investigated using molecular docking against tubulin, and 8h and 10k showed the best interactions with tubulin of all the drugs tested. [ABSTRACT FROM AUTHOR]

The aim. This review aims to provide a comprehensive understanding of dichloroacetic acid derivatives. We aim to cover all aspects of these compounds, including their chemical properties, various synthesis methods, and their wide range of applications in medicinal chemistry. By exploring their diverse roles in drug development, we aim to highlight their importance and potential in shaping future pharmaceutical innovation. Materials and methods. Bibliosemantic and analytical methods are used in the research. Results. Our studies confirm the potential effectiveness of dichloroacetic acid and its derivatives in the treatment of cancer and other diseases. These compounds can induce the apoptosis process, which is the programmed cell death, and inhibit the cancer cells' growth. This is particularly effective when dichloroacetic acid and its derivatives are used in combination with other therapeutic methods, as indicated in the patents cited in our study. Dichloroacetic acid and its derivatives have also shown the ability to lower blood glucose and cholesterol levels. This indicates the possibility of their use for diabetes, hyperlipidemia, and lactic acidosis treatment. Diabetes, hyperlipidemia, and lactic acidosis are serious conditions that can lead to significant health problems. Therefore, the possibility of using dichloroacetic acid and its derivatives for the treatment of these conditions opens new perspectives in medical science. Conclusions. Our findings point to the prospects of further research in the field of new therapy methods development and the use of dichloroacetic acid derivatives as potential drugs to improve the effectiveness of cancer and other diseases treatment. We believe that these compounds have great potential for further study and may play an important role in future medical innovation. [ABSTRACT FROM AUTHOR]

This article discusses the synthesis of hybrid molecules that contain both γ-butyrolactone and γ-butyrolactam motifs, which are important in pharmaceutical science. The authors developed a method for regioselective difunctionalization of deconjugated butyrolactones using α-amide enones as Michael acceptors, resulting in high yields and excellent diastereoselectivity. The study provides a simple and efficient approach to the synthesis of these hybrid molecules. Additionally, the article briefly mentions the celebration of Yamamoto's 80th birthday, but does not provide any further details about the event or Yamamoto himself. [Extracted from the article]

A series of novel 2-oxo-2-(arylamino)ethyl 4-formylbenzoates were prepared via the reaction of the potassium salt of p-formylbenzoic acid with 2-chloro-N-aryl-acetamide in DMF at reflux. A new series of 1,4- dihydropyridin-3,5-dicarbonitriles, hexahydroacridine-1,8-diones, decahydropyrimido[4,5-b]quinolines, and hexahydrobenzo[4,5]imidazo[2, 1-b]quinazolines which are linked to N-aryl-benzoyloxyacetamide were obtained through the Hantzsch reaction of various 2-oxo-2-(arylamino)ethyl 4-formylbenzoate with the respective 3-aminocrotononitrile or a mixture of 1,3-dicarbonyl compounds and amine source. The structures of the novel compounds were confirmed using a variety of spectra. [ABSTRACT FROM AUTHOR]

Antibiotic resistance associated with various microorganisms such as Gram‐positive, Gram‐negative, fungal strains, and multidrug‐resistant tuberculosis increases the risk of healthcare survival. Preliminary therapeutics becoming ineffective that might lead to noteworthy mortality presents a crucial challenge for the scientific community. Hence, there is an urgent need to develop hybrid compounds as antimicrobial agents by combining two or more bioactive heterocyclic moieties into a single molecular framework with fewer side effects and a unique mode of action. This review highlights the recent advances (2013–2023) in the pharmacology of rhodanine‐linked quinoline hybrids as more effective antimicrobial agents. In the drug development process, linker hybrids acquire the top position due to their excellent π‐stacking and Van der Waals interaction with the DNA active sites of pathogens. A molecular hybridization strategy has been optimized, indicating that combining these two bioactive moieties with an arylidene and an amino spacer linker increases the antimicrobial potential and reduces drug resistance. Moreover, the structure–activity relationship study is discussed to express the role of various functional groups in improving and decrementing antimicrobial activities for rational drug design. Also, a linker approach may accelerate the development of dynamic antimicrobial agents through molecular hybridization. [ABSTRACT FROM AUTHOR]

The increasing cases of drug resistance and high toxicity associated with the currently used antifungal agents are a worldwide public health concern. There is an urgent need to develop new antifungal drugs with unique target mechanisms. Plant-based compounds, such as carvacrol, eugenol, coumarin, cinnamaldehyde, curcumin, thymol, etc., have been explored for the development of promising antifungal agents due to their diverse biological activities, lack of toxicity, and availability. However, researchers around the world are unable to fully utilize the potential of natural products due to limitations, such as their poor bioavailability and aqueous solubility. The development of hybrid molecules containing natural products is a promising synthetic approach to overcome these limitations and control microbes' capability to develop resistance. Based on the potential advantages of hybrid compounds containing natural products to improve antifungal activity, there have been different reported synthesized hybrid compounds. This paper reviews different literature to report the potential antifungal activities of hybrid compounds containing natural products. [ABSTRACT FROM AUTHOR]

Anti-inflammatory drugs are used to relieve pain, fever, and inflammation while protecting the cardiovascular system. However, the side effects of currently available medications have limited their usage. Due to these adverse effects, there is a significant need for new drugs. The current trend of research has shifted towards the synthesis of novel anthranilic acid hybrids as anti-inflammatory agents. Phenyl- or benzyl-substituted hybrids exerted very good anti-inflammatory effects in preventing albumin denaturation. To confirm their anti-inflammatory effects, additional ex vivo tests were conducted. These immunohistochemical studies explicated the same compounds with better anti-inflammatory potential. To determine the binding affinity and interaction mode, as well as to explain the anti-inflammatory activities, the molecular docking simulation of the compounds was investigated against human serum albumin. The biological evaluation of the compounds was completed, assessing their antimicrobial activity and spasmolytic effect. Based on the experimental data, we can conclude that a collection of novel hybrids was successfully synthesized, and they can be considered anti-inflammatory drug candidates—alternatives to current therapeutics. [ABSTRACT FROM AUTHOR]

Hybrid molecules of pharmacophores could enhance the desired pharmacological activity while minimizing the side effects and drug resistance associated with individual pharmacophores. In this study, we synthesized twelve bis-1,2,3-triazole-based chalcones (78–90 %) yield) in five steps and characterized them via IR, 1H NMR, 13C NMR, and HRMS spectroscopy. Seven hybrid molecules demonstrated good cytotoxicity against A-549 lung cancer cells in the MTT cell viability assay (IC50 = 44.72±0.66 to 86.22±1.06 µM), which is comparable to the IC50 of the anticancer drug doxorubicin (39.86±1.15 µM). Molecular docking studies of the hybrid molecules with extracellular signal-regulated kinase 2/mitogen-activated protein kinase 1 (ERK2) (PDB ID: 4ZXT), which is triggered by lung cancer, showed excellent binding interactions (H-bonding, hydrophobic interactions, halogen bonding, etc.) between the drug candidates and target receptors (binding energy = −7.7 to −9.7 kcal/mol). We believe that these hybrid molecules could have potential applications as anticancer agents.

A new series of indazole-indolizine-triazine hybrid molecules was obtained by [3 + 2] cycloaddition reaction between newly synthesized nitrogen ylides with indazole skeleton and previously reported dipolarophile 2‐ethynyl‐4,6‐dimethoxy‐1,3,5‐triazine and fully characterized. The biological evaluation of hybrids revealed good antitumor growth inhibitory activity against UO-31 renal cancer cell line for the (1H-indazole-1-yl)(1-(4,6-dimethoxy-1,3,5-triazin-2-yl)-7-methylindolizin-3-yl)methanone derivative 7a. Also, for the same compound, a moderate farnesyltransferase inhibitory activity (IC50 = 52.50 ± 16.07 µM) was observed. However, the best result as farnesyltransferase inhibitor of the series was registered for the 5-bromoindazole substituted analogue 7e (IC50 = 27.08 ± 4.93 µM).

Cancer is a devastating disease, but advancements in cancer treatment offer hope for the future. Aurora kinases are a family of serine/threonine kinases that play critical roles in cell cycle control and mitosis. There are three members of the Aurora kinase family in humans: Aurora-A kinase, Aurora-B kinase, and Aurora-C kinase. This study focuses on the synthesis of hybrid compounds combining adamantane and 1,3,4-oxadiazole as potential inhibitors of Aurora-A kinase. A series of novel 4-((5-((3r,5r,7r)-adamantan-1-yl)-1,3,4-oxadiazol-2-yl)thio)-N,N-2-yn-1-amine were synthesized and evaluated against Aurora-A kinase. The most potent derivatives were 6a and 6k with IC50 values 36.6 and 38.8 μM, respectively. Docking studies probed the binding interactions of these compounds within the active site of the kinase. The findings contribute to the development of novel cancer therapeutics and offer promise for more effective and targeted treatments in the future. [ABSTRACT FROM AUTHOR]

A series of novel artemisinin-isatin hybrids (7a-t) linked via different lengths of esters were designed, synthesized and evaluated for their cytotoxicity against human myeloid leukemia cell lines (K562 and K562/ADR), human acute lymphoblastic leukemia cell line (CCRF-CEM), as well as normal human peripheral blood mononuclear cells (PBMCs) using the MTT assay. The initial results demonstrated that most of the ester-tethered artemisinin-isatin hybrids (IC50: 1.53–51.39 µM) showed activity against CCRF-CEM cells, with six of them (IC50: 3.47–9.52 µM) being >10.5 times more potent than artemisinin (IC50: >100 µM). Notably, hybrid 7i (IC50: 3.82, 1.53, and 22.71 µM) exhibited promising activity against all three tested leukemia cell lines. Hybrid 7i was 3.2 and 2.5 times more active than Adriamycin (IC50: 4.89 µM) and Vorinostat (IC50: 3.83 µM) against K562 cells, respectively, and >4.4 times more effective than Adriamycin (IC50: >100 µM) against K562/ADR cells. Moreover, hybrid 7i (IC50: >100 µM) showed no toxicity towards PBMCs, with an SI value > 26.17, indicating excellent safety and selectivity profiles. Additionally, hybrid 7i displayed acceptable pharmacokinetic properties. In summary, hybrid 7i is a promising lead molecule for the development of novel anti-leukemic agents with low toxicity and high selectivity. [ABSTRACT FROM AUTHOR]

To investigate the impact of alkyl linkers of different lengths between dihydroartemisinin and isatin moieties on the anti-breast cancer activity, a series of twenty dihydroartemisinin-isatin hybrids with three- and four-carbon alkyl linkers were synthesized and screened against drug-sensitive MCF-7 and MDA-MB-231 breast cancer cell lines, as well as their multidrug-resistant counterparts MCF-7/ADR and MDA-MB-231/ADR cell lines. The results showed that the length of the carbon spacer had a significant effect on the anti-breast cancer activity, with hybrids tethered through a four-carbon linker exhibiting greater potency than their three-carbon analogs. Additionally, substituents at C-3 and C-5 positions of isatin moiety also greatly influenced the activity, with fluoro at C-3 position and methoxime/ethoxime at C-5 position being favorable for activity. These enriched structure–activity relationships may facilitate the rational design of future compounds. [ABSTRACT FROM AUTHOR]

Cancer is one of the most deadly diseases worldwide, challenging the world for effective treatment of the diseases, to tackle this problem a vast amount of therapeutic candidates are being investigated. Indolebenzimidazole structures have recently gained considerable attention, because compounds containing these structure exhibit a very good anticancer property. Two series of novel indole-benzimidazole hybrids molecules viz., 2-(5-substituted-1H-indol-3-yl)-5-substituted-1H-benzo[d]imidazole 5(a-f) and 2-(5-substituted-1-(3-methylbut-2-enyl)-1H-indol-3-yl)-5-substituted-1H-benzo[d]imidazole 6(a-f) were synthesized and characterized by spectroscopic techniques. The twelve target molecules have been investigated for their in-vitro cytotoxic activity against human ovarian carcinoma cells (SKOV-3), human prostate cancer cells (PC-3), human cervical cancer cells (HeLa) and human acute monocytic leukemia cells (THP-1) using MTT assay. Compound; 2-(5-bromo-1H-indol-3-yl)-5-methyl-1H-benzo[d]imidazole (5e) was interesting with IC50 (µM) values of 23.69 (SKOV-3), 73.05 (PC-3), 64.66 (HeLa) and 39.08 (THP-1), respectively. [ABSTRACT FROM AUTHOR]

Background: The design and synthesis of hybrid molecules will explore finding new drugs. Objectives: The synthesized hybrid molecules to evaluate their biological properties. Methods: Apply click chemistry to tether flavonols and benzenesulfonamide. Results: Two drug candidates show potential against lung cancer. Conclusions: Two drug candidates did not affect the normal cells and provided a new drug design route. [ABSTRACT FROM AUTHOR]

In this study, an efficient one-pot, solvent-free synthesis of pyrazolone-1,3-dithiolan and pyrazolone-1,3-dithiole hybrids from the reaction between in situ generated pyrazolones and propargyl bromide in the presence of carbon disulfide is reported. This reaction was carried out in the presence of triethylamine at room temperature, and new pyrazolone-1,3-dithiolan and pyrazolone-1,3-dithiole hybrids were formed in good to high yields. In the 1H NMR spectra of synthesized 1,3-dithiole hybrid molecules, the signal of olefinic hydrogen appeared at about 7.07–7.41 ppm in DMSO-d6. The values of these chemical shifts indicate that both linked pyrazole and dithiole rings in the dithiole-pyarzolone hybrid molecules have aromatic properties. [ABSTRACT FROM AUTHOR]

Twelve novel neo-tanshinlactone-chalcone hybrid molecules were constructed through a versatile methodology involving the Horner-Wadsworth-Emmons (HWE) olefination of 4-formyl-2H-benzo [h]chromen-2-ones and phosphonic acid diethyl esters, as the key step, and evaluated for anticancer activity against a series of four breast cancers and their related cell lines, viz. MCF-7 (ER + ve), MDAMB-231 (ER-ve), HeLa (cervical cancer), and Ishikawa (endometrial cancer). The title compounds showed excellent to moderate in vitro anti-cancer activity in a range of 6.8-19.2 μM (IC50). Compounds 30 (IC50 = 6.8 μM and MCF-7; IC50 = 8.5 μM and MDA-MB-231) and 31 (IC50 = 14.4 μM and MCF-7; IC50 = 15.7 μM and MDA-MB-231) exhibited the best activity with compound 30 showing more potent activity than the standard drug tamoxifen. Compound 30 demonstrated a strong binding affinity with tumor necrosis factor α (TNF-α) in molecular docking studies. This is significant because TNFα is linked to MCF-7 cancer cell lines, and it enhances luminal breast cancer cell proliferation by upregulating aromatase. Additionally, virtual ADMET studies confirmed that hybrid compounds 30 and 31 met Lipinski's rule; displayed high bioavailability, excellent oral absorption, favorable albumin interactions, and strong penetration capabilities; and improved blood-brain barrier crossing. Based on the aforementioned results, compound 30 has been identified as a potential anti-breast cancer lead molecule. [ABSTRACT FROM AUTHOR]

The present article focuses on the synthesis and biological evaluation of a novel anthranilic acid hybrid and its diamides as antispasmodics. Methods: Due to the predicted in silico methods spasmolytic activity, we synthesized a hybrid molecule of anthranilic acid and 2-(3-chlorophenyl)ethylamine. The obtained hybrid was then applied in acylation with different acyl chlorides. Using in silico analysis, pharmacodynamic profiles of the compounds were predicted. A thorough biological evaluation of the compounds was conducted assessing their in vitro antimicrobial, cytotoxic, anti-inflammatory activity, and ex vivo spasmolytic activity. Density functional theory (DFT) calculation, including geometry optimization, molecular electrostatic potential (MEP) surface, and HOMO-LUMO analysis for the synthesized compounds was conducted using the B3LYP/6–311G(d,p) method to explore the electronic behavior, reactive regions, and stability and chemical reactivity of the compounds. Furthermore, molecular docking simulation along with viscosity measurement indicated that the newly synthesized compounds interact with DNA via groove binding mode. The obtained results from all the experiments demonstrate that the hybrid molecule and its diamides inherit spasmolytic, antimicrobial, and anti-inflammatory capabilities, making them excellent candidates for future medications. [ABSTRACT FROM AUTHOR]

Dengue fever is a viral ailment mostly found in tropical and sub-tropical communities. Dengue fever is spread by the mosquito Aedes aegypti. According to WHO reports, more than 12,000 people perish because of this disease yearly. At present, there is no officially certified drug for the cure of dengue. Dengue virus (DENV) holds four distinct serotypes and hence the development of a single molecule effective against all these types is a difficult task. Various new molecules have been developed against DENV. In this review, we have summarised new chemical scaffolds that have been tested against DENV. New molecules addressed in this review can be considered as a lead compound for upcoming drug development against DENV. [ABSTRACT FROM AUTHOR]

In this study, new indenopyrimidin-1,2,4-triazol derivatives were synthesized in high yields using multicomponent reactions of ninhydrins, guanidine, alkyl bromides, aldehydes and hydrazonoyl chloride in the presence of Fe3O4/CuO/ZnO@Multi-Walled Carbon Nanotube Magnetic Nanocomposites (Fe3O4/CuO/ZnO@MWCNT MNCs) as a high performance catalyst in water at room temperature. The Fe3O4/CuO/ZnO@MWCNT MNCs was prepared using Petasites hybridus rhizome water extract as a green media and moderate base. This procedure had some benefits such as short reaction time, products with excellent yields, simple catalyst and products separation. The Fe3O4/CuO/ZnO@MWCNT MNCs was showed a good improvement in the yield of the product and displayed significant reusable activity as well. Investigation of antioxidant ability of synthesized compounds using radical trapping of diphenyl-picrylhydrazine (DPPH) and ferric reduction power experiment were another purpose in this research. Green chemistry is the use of a set of principles to reduce or eliminate the use or generation of unsafe materials in the design, fabrication and applications of chemical products. Among solvents, water is a green solvents and very suitable for performing organic reaction. The present procedure avoids the use of toxic solvent. Substituted 1,2,4-triazoles and their derivatives are key skeleton of many biologically active molecules and important organic compounds that exhibit wide applications in pesticides, medicines, functional materials and organocatalysts. [ABSTRACT FROM AUTHOR]

In order to combat microbial infections and to address the issue of multi-drug resistance, a class of novel piperidine-bearing cinnamic acid hybrids 4a–4l were synthesized and validated using various spectroscopic techniques like IR, NMR, and mass spectrometry. In addition, the compounds were assessed for antimicrobial activity. Compound 4l demonstrated significant activity against Pseudomonas aeruginosa and Escherichia coli strains with MIC = 50 and 12.5 µg/mL, and compounds 4a, 4d, 4e, and 4l exhibited considerable activity against all fungal strains ranging from MFC = 125–250 µg/mL. An in silico ADMET study indicated that most compounds show favorable drug-like and toxicological properties. Furthermore, a molecular docking study revealed that compounds 4d, 4e, 4h, and 4j could be lodged in the active pocket and inhibit human fungal Candida albicans Hsp90 NBD protein via various interactions, and results indicated the synthesized analogs to be promising lead compounds in the search for novel antifungal drug-like molecules to be orally bioavailable. [ABSTRACT FROM AUTHOR]

Eleven two-carbon tethered artemisinin–isatin hybrids (4a–k) were designed, synthesized, and evaluated for their antiproliferative activity against MCF-7, MDA-MB-231, and MDA-MB-231/ADR breast cancer cell lines, as well as cytotoxicity toward MCF-10A cells in this paper. Among them, the representative hybrid 4a (IC50: 2.49–12.6 µM) was superior to artemisinin (IC50: 72.4->100 µM), dihydroartemisinin (IC50: 69.6–89.8 µM), and Adriamycin (IC50: 4.46–>100 µM) against the three tested breast cancer cell lines. The structure–activity relationship revealed that the length of the alkyl linker between artemisinin and isatin was critical for the activity, so further structural modification could focus on evaluation of the linker. The in silico studies were used to investigate the mechanism of the most promising hybrid 4a. Target prediction, bioinformatics, molecular docking, and molecular dynamics revealed that the most promising hybrid 4a may exert anti-breast cancer activity by acting on multiple targets such as EGFR, PIK3CA, and MAPK8 and thus participating in multiple tumor-related signaling pathways.

In this study, 13 new hybrid compounds (7a-m) were synthesised starting from ursolic acid, and their cytotoxic activities were investigated on the BEAS-2B and A549 cell lines. In addition, the synthesised compounds were tested against Staphylococcus aureus, Escherichia coli, and Candida albicans to determine their anti-microbial properties. The hybrid compounds that exhibited the lowest cytotoxicity against the BEAS-2B were 7k, 7b, and 7g. The cytotoxicity of the compounds against A549 was evaluated, the IC50 value of 7k, 7b, and 7g are found as 0.15 µM, 0.31 µM, and 0.26 µM, respectively. The results showed that the selectivity of 7k was 7 times higher than doxorubicin against the A549 cells. According to the antimicrobial activity studies 7c is found as the most effective compound against S. aureus. Almost all compounds showed a similar inhibition potential against E. coli and C. albicans. [ABSTRACT FROM AUTHOR]