Compounds 3a Research Articles

Identification of Oral Bioavailable Coumarin Derivatives as Potential AR Antagonists Targeting Prostate Cancer.

Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1, which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC50 = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC50 = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, 4a showed superior efficacy against ARF876L/T877A and ARW741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles (F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.

Synthesis of 1,10-phenanthroline-2,9-bistriazoles: Evaluation as G-quadruplex binders and anti-tumor activity.

Novel 1,10-phenanthroline-2,9-bistriazoles derivatives have been synthesized by copper-catalyzed azide/alkyne cycloaddition reactions and assessed for their ability to bind and stabilize G-quadruplex (G4) structures. Ten novel compounds were evaluated using Förster resonance energy transfer (FRET) melting, circular dichroism (CD), and fluorescence spectroscopy on several G4 sequences. Biophysical characterization led to the identification of compounds 4a, 4b, and 5b as good G4 ligands of KRAS G4 sequences. The cell viability of all derivatives was also assessed, revealing weak effects. However, compound 2a exhibited cytotoxicity activity on A549 and H1299 cancer cells and low cytotoxicity towards non-malignant cells MRC-5 not connected with its G4-binding ability. Flow cytometry showed that 2a induced a cell viability decrease in S and G2/M phases for A549 and H1299; thus, more studies should be performed to explore the proteins involved in cell cycle regulation.

Exploring the selective incorporation of 15β-senecioyloxi-ent-kaurenoic acid methyl ester in Langmuir monolayers mimicking cell membranes

A natural product isolated from Brazilian plant species Baccharis retusa (Asteraceae), 15β-senecioyloxi-ent-kaurenoic acid (1), demonstrated activity against trypomastigotes of the parasite Trypanosoma cruzi but it was inactive against intracellular forms. In the present work, compound 1a, a methyl ester derivative of 1, exhibited activity against intracellular amastigotes (EC50 = 11.8 μM), similar to that determined by positive control benznidazol (EC50 = 16.2 μM) and reduced toxicity against NCTC cells (CC50 > 200 μM). Based on this selectivity, compound 1a was incorporated into Langmuir monolayers of three lipids, DPPC, DPPE, and DPPS, to characterize the interaction of the compound with each lipid as model for cell membranes. For that, we used tensiometry, surface potential measurements, and infrared spectroscopy. Our results showed that incorporating the drug into DPPC monolayers significantly altered the physicochemical properties, resulting in more condensed monolayers. In contrast, the incorporation of the drug into DPPE and DPPS monolayers led to their expansion. The effects on DPPC were more pronounced than on the other lipids, inducing a viscoelastic monolayer with lower alignment of the alkyl chains, as observed through surface potential measurements and infrared spectroscopy. These changes indicate a more cohesive DPPC monolayer upon drug incorporation, forming domains in a strip shape. We believe these results contribute to understanding the interaction between 1a and lipid interfaces, especially those involved in biological interactions with amastigotes of parasite T. cruzi.

Isolation of Natural Veratrylidenehydrazide Compound from Wedelia Biflora and Synthesis of Veratrylidenehydrazide Analogue: Investigation of Larvicidal Activity Against Culex Quinquefasciatus and Toxicity Analysis in Nontarget Aquatic Species

AbstractIn this study, veratrylidenehydrazide was isolated from Wedelia biflora, and compounds (1a, 2a, and 3a–j) were synthesised to evaluate their larvicidal and antifeedant activities. Veratrylidenehydrazide 1a was verified using GC‐MS. The veratrylidenehydrazide analogues 2a and 3a–j were synthesised via a condensation method with yield range 71%–92%. The compounds (1a, 2a, and 3a–j) were synthesised and characterised through FT–IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. Veratrylidenehydrazide 1a was verified using GC‐MS analysis. Natural veratrylidenehydrazide compound 1a and the synthesised veratrylidenehydrazide analogues (2a, 3a–j) were screened for larvicidal activity against Culex quinquefasciatus. The larvicidal activity of compound 3g was found to be highly active, while low toxicity was observed against Oreochromis mossambicus nontarget aquatic species compared to natural veratrylidenehydrazide. Compound 3g exhibited a higher binding affinity (−8.8 kcal/mol) compared to standard of temephos (−4.5 kcal/mol), equipotential binding affinity against permethrin (−9.1 kcal/mol), and diflubenzuron (−8.5 kcal/mol). Lead molecules have larvicidal properties, and their use as insecticides makes them important.

Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A

The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO4) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC50] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO4, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC50 = 1.0 μg/mL) and A. pacificum (EC50 = 0.47 μg/mL), being 3–5-fold more potent than natural bacillamide A, Diuron, and CuSO4. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO4 and provides a promising candidate for the development of new algicides, worthy of further investigation.

Quinoline Based thiazolidinediones: Design, Synthesis, In Silico, In Vitro, Antioxidant and Antidiabetic Evaluation

AbstractIn the present research work a sequence of substituted quinoline based thiazolidinedione moieties (12a–h) were designed and synthesized as potential antidiabetic agents. Pancreatic α‐amylase (PAA) and intestinal α‐glucosidase (IAG) enzymes were considered as potential targets for effective treatment of diabetes. The potential of all compounds (12a–h) was assessed in vitro against PAA and IAG using acarbose as standard. The results suggested that compound 12h has shown superior PAA and IAG inhibitory activity with respective to standard (IC50 = 4.683 ± 0.06 µM and 2.456 ± 0.07 µM). Furthermore, using computational (in silico) studies like AutoDock and Desmond, predicted the significant binding interactions responsible for the activity of all compounds (12a–h) at the active site of enzymes, while SwissADME and Osiris property explorer tools computed in silico drug likeliness and toxicity properties. The RMSD, RMSF, Rg and protein ligand contacts, confirmed the stable binding of compound 12h and 12g with the both PAA and IAG proteins. The in silico results confirmed the 12h molecule as a superior drug with high binding affinity and good drug likeness against PAA and IAG, confirming in vitro results. We also studied antioxidant activity (AOA) of all synthesized compounds and results confined that the compound 12h has good antioxidant potential (IC50 = 5.04 ± 0.054 µM) among all other compounds. In conclusion, in vitro, in silico and antioxidant studies revealed 12h compound was found to be potential compound.

Naphthoindole-2-carboxamides as a lipophilic chemotype of hetarene-anthraquinones potent against P-gp resistant tumor cells

The acquisition of multidrug resistance (MDR) to chemotherapy is a major obstacle to successful cancer treatment. Aiming to improve the potency of anthraquinone-derived antitumor compounds against MDR cancer cells, we employed a rational design approach to develop new heteroarene-fused anthraquinones. Shifting the carboxamide group in the naphtho[2,3-f]indole scaffold from the 3-position to 2 increased the lipophilicity and P-glycoprotein (P-gp) binding of the derivatives, potentially enhancing their ability to circumvent P-gp-mediated MDR. To validate the computations, we developed a scheme for heterocyclization into esters of naphtho[2,3-f]indole-2-carboxylic acid, based on the 5-endo-dig cyclization of 2-alkynyl-3-amino-1,4-dimethoxyanthraquinone under mild basic conditions using tetra-n-butylammonium fluoride (TBAF). The synthesized naphthoindole-2-carboxamides, particularly compound 1a bearing (S)-3-aminopyrrolidine in the carboxamide fragment, demonstrated the highest antiproliferative activity. Most importantly, 1a suppressed the growth of the P-gp-positive K562/4 leukemia tumor cell line (resistance index = 2.4), while its 3-isomer LCTA-2640 and Dox did not (RI = 125 and 140, respectively). Studies of intracellular uptake and distribution showed that 1a, unlike its 3-substituted isomer, effectively accumulated in resistant tumor cells, confirming the correlation between in silico and experimental data. The lead compound 1a interacts with DNA duplex and inhibits topoisomerase 1 but does not induce oxidative stress. Treatment with 1a increases the population of apoptotic cells in both K562 and K562/4 sublines, regardless of the cell cycle phase. Taken together, this work provides an interesting example of how a little modification in chemical structure can lead to striking differences in antitumor properties. In conclusion, we have identified a potent class of compounds that offer distinct advantages in combating resistant tumor cells.

Synthesis and Docking Studies of Novel Spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione Derivatives

In this study, a set of spiro[5,8-methanoquinazoline-2,3′-indoline]-2′,4-dione derivatives 3a–p were synthesized starting from unsubstituted and N-methyl-substituted diendo- and diexo-2-aminonorbornene carboxamides, as well as various substituted isatins. The typical method involves a condensation reaction of alicyclic aminocarboxamide and isatin in the presence of a catalyst, using a solvent and an acceptable temperature. We developed a cost-effective and ecologically benign high-speed ball milling (HSBM), microwave irradiation (MW), and continuous flow (CF) technique to synthesize spiroquinazolinone molecule 3a. The structures of the synthesized compounds 3a–p were determined using 1D and 2D NMR spectroscopies. Furthermore, docking studies and absorption, distribution, metabolism, and toxicity (ADMET) predictions were used in this work. In agreement with the corresponding features found in the case of both the SARS-CoV-2 main protease (RCSB Protein Data Bank: 6LU7) and human mast cell tryptase (RCSB Protein Data Bank: 2ZA5) based on the estimated total energy and binding affinity, H bonds, and hydrophobicity in silico, compound 3d among our 3a–g, 3i–k, and 3m derivatives was found to be our top-rated compound.

Synthesis, Aromatase Inhibition, Cytotoxicity and Molecular Docking Studies of New Fluorinated and Non-fluorinated Thiourea Derivatives of Desloratadine.

Aromatase inhibitors are among the most effective treatment of the breast cancer. Aromatase catalyzes estrogen biosynthesis, which is a long-term cause of breast cancer. Current study describes the synthesis, purification of 26 new fluorinated and non-fluorinated thiourea derivatives of desloratadine (5), and their aromatase inhibition activity, cytotoxicity against cancer cell line (MDA-MB-231). Compounds 7v and 7l exhibited a significant anti-aromatase activity, while compounds 7a, 7g-h, 7m and 7u were also significant active against MDA-MB-231 cell line. Furthermore, the molecular docking studies revealed that active compounds form key interactions with the crucial amino acid of aromatase active site including TRP224, LEU477, CYS437, ALA438, MET374, ARG115, ILE305, and PHE221, which are responsible for the binding interaction of aromatase. All analogues were new, except 7b and 7k and also lacked cytotoxicity BJ human fibroblasts, with the exception of 5 and 7x. This selectivity makes this series particularly interesting for further studies.

β-Carboline-3-carboxamide Antimalarials: Structure-Activity Relationship, ADME-Tox Studies, and Resistance Profiling.

The development of parasite resistance to both artemisinin derivatives and their partner drugs jeopardizes the effectiveness of the artemisinin combination therapy. Thus, the discovery of new antimalarial drugs, with new mechanisms of action, is urgently needed. We recently disclosed that β-carboline 1a was orally efficacious in Plasmodium berghei-infected mice and that it showed low cross-resistance between susceptible Plasmodium falciparum and four different drug-resistant strains. In this report, we describe the synthesis and in vitro antimalarial evaluation of 91 new derivatives of 1a. The asexual blood stage growth inhibition data show a clear preference for a 3,4-dihalogenated, 3,5-dihalogenated, 3,4,5-trichloro-, or 4-trifluoromethyphenyl ring at the C1-position. The most potent compound, 3,4,5-trichlorophenyl-substituted 42a, is twice as potent as 1a. Six potent analogues were assessed for their drug-like properties, and four of these were subjected to in vitro barcoded cross-resistance profiling. Compounds 1a, 1m, 42a, and 42m showed no cross-resistance to 32 resistance mutations on the Dd2 genetic background and 10 resistance mutations on the 3D7 genetic background. These data suggest that compounds in this scaffold possess a novel mechanism of antimalarial action.

One-pot synthesis of new benzo[4,5]imidazo[1,2-a]pyrimidines and pyrazolo[1,5-a] pyrimidines as an eco-friendly and effective method catalyzed by acetic acid with prospective antimicrobial agents

A novel set chalcones 3a-d was efficiently synthesized in elevated produces across the condensing process of Claisen-Schmidt. An eco-friendly and efficient process was designed for creating a novel desired products 5a-f and 7a-f, respectively with excellent yields. This synthesis was accomplished by reacting acetophenone derivatives 1a-d, heteroaromatic aldehydes 2a,b and aminobenzoimidazole 4 or 3-aminopyrazole 6a,b, using acetic acid as both the catalyst and solvent. Solvent optimization was performed during the synthesis of the desired compounds 5a or 7a, highlighting the benefits of using acetic acid that is harmless for the environment, which offers easy procedure, rapid reaction, elevated efficiency and broad tolerance of starting materials. The preferred products were verified through compatible spectroscopic data. The antimicrobial efficacious for all compounds was successfully evaluated against various microorganisms, revealing that 3b exhibited significant antimicrobial activity across all tested microbes, with measurements of the minimum inhibitory concentrations being between 4.80 to 63.8 μM.

Semi-Preparation and X-ray Single-Crystal Structures of Sophocarpine-Based Isoxazoline Derivatives and Their Pesticidal Effects and Toxicology Study.

Recently, research and development of novel pesticides from natural plant products have received much attention. To accelerate the application of sophocarpine as the agrochemical candidate, a series of novel sophocarpine-based isoxazoline derivatives were prepared by the 1,3-dipolar [2 + 3] cycloaddition reaction of sophocarpine with different chloroximes. Their structures were well characterized by high-resolution mass spectra, infrared spectra, and proton/carbon-13 nuclear magnetic resonance spectra. Eight steric configurations of compounds 5a, 5e', 5f, 5g, 5h, 5i, 5r, and 5u' were further determined by X-ray single-crystallography. Against Aphis citricola Van der Goot, compounds 5n (LD50: 0.032 μg/nymph) and 5o (LD50: 0.024 μg/nymph) exhibited greater than 3.7- and 4.9-fold potent aphicidal activity compared to sophocarpine (LD50: 0.118 μg/nymph). Against Tetranychus cinnabarinus Boisduval, derivative 5g displayed the most promising acaricidal activity with the LC50 value of 0.247 mg/mL, which was 14.2-fold that of sophocarpine. Compounds 5d and 5g also exhibited good control efficacy against T. cinnabarinus. Scanning electron microscopy images indicated that compound 5g can destroy the mite cuticle layer. These results will provide the foundation for the structural modification and use of sophocarpine derivatives as agrochemicals in the future.

Synthesis, Antibacterial, Anti-Biofilm Properties, and Docking Study of Indeno[1,2-b]Pyridin-5-One Derivatives

In this context, we designed and synthesized a series of hydrazonal and their related indeno[1,2-b]pyridin-5-one derivatives to investigate their antibacterial and anti-biofilm properties. Several of the synthesized compounds exhibited significant efficacy against all microorganism species tested. Most of the compounds demonstrated favorable results when tested against Gram-positive bacteria. The derivatives 4a, 4f, 6c, and 6f exhibit the highest antimicrobial efficacy, as indicated by their minimum inhibitory concentration (MIC) values ranging from 4 to 512 μg/mL. We conducted additional investigations on 4a, 6c, and 6f for the purpose of examining their synergy using Checkerboard assay. Compound 6c demonstrated a synergistic impact against methicillin-sensitive Staphylococcus aureus (MSSA) and Pseudomonas aeruginosa, while exhibiting moderate synergistic activity against methicillin-resistant Staphylococcus aureus (MRSA). In addition, the simultaneous use of gentamycin with compounds 4a and 6f demonstrates a synergistic impact in fighting against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, respectively. Three chosen compounds were evaluated for their antibiofilm efficacy. Application of 4a, 6c, and 6f effectively reduced the production of biofilms in MRSA, MSSA, and Pseudomonas aeruginosa, resulting in a significant decrease compared to the untreated samples. In addition, ADME and pharmacokinetic analyses were conducted for the three most potent derivatives, namely 4a, 6c, and 6f. Compounds 4a and 6c were subjected to docking in the LasR Quorum-Sensing Receptor, whereas compounds 6c and 6f were docked in the sortase enzyme.

Design, synthesis, and biological investigations of new pyrazole derivatives as VEGFR2/CDK-2 inhibitors targeting liver cancer

New Series of N-Manniche bases 3,4 (a-c) and 5,6 (a-b) were synthesized through the reaction of benzaldehyde and amine with 3-methyl-4-(aryldiazenyl)-1H-pyrazol-5-ol derivatives 2(a-c), they were fully characterized by FT-IR, (1H, 13C) NMR data in addition to their mass spectra. The Structural Activity Relationship of the target compounds were examined for their cytotoxicity. Some newly synthesized compounds showed promising antiproliferation properties when tested against HepG2 cancer cells. Compounds 4a, 5a, and 6b showed potent cytotoxicity against HepG2 with IC50 values of 4.4, 3.46 and 2.52 µM compared to Sorafenib (IC50 = 2.051 µM) and Roscovitine (IC50 = 4.18 µM). Furthermore, they were safe against the THLE2 cells with higher IC50 values. Compound 6b exhibited promising dual VEGFR2/CDK-2 inhibition activities; it had an IC50 value of 0.2 μM with VEGFR2 inhibition of 93.2%, and it had an IC50 value of 0.458 μM with CDK-2 inhibition of 88.7%. In comparison to the untreated control group (0.95%), compounds 5a (38.32%) and 6b (42.9%) considerably increased the cell population in total apoptosis. In addition, compounds 5a and 6b arrested the cell population at G0-G1 and S phases, respectively. Molecular docking experiments confirmed the virtual binding mechanism of the most active drugs, which were found to have good binding affinities with both receptor active sites.

Design, synthesis, anti-trypsin and anti-inflammatory evaluation of new guanidinobenzoic acid ester derivatives

Herein, we designed a series of guanidinobenzoic acid ester derivatives on the basis of approved AP drugs, such as nafamostat, gabexate and camostat, and evaluated their inhibitory effects on trypsin and anti-inflammatory activity. Among them, five compounds (6a, 6c–6e, 7j) showed excellent inhibitory effects on trypsin with IC50 values of 0.0756 μM to 0.1227 μM, which are more potent than nafamostat and gabexate. Moreover, compounds 6a, 6b and 6c also showed significant inhibitory potency against the pro-inflammatory molecule NO with IC50 values of 1.618 μM, 2.276 μM, and 3.022 μM, respectively. Consequently, the potential lead compounds simultaneously with anti-trypsin and anti-inflammatory activities were identified, which would profit further structural optimization for the treatment of AP.

Green synthesis, molecular docking and in vitro biological evaluation of novel hydrazones, pyrazoles, 1,2,4-triazoles and 1,3,4-oxadiazoles

Ultrasonic waves were used for synthesis of novel hydrazones, bishydrazones, pyrazoles, 1,2,4-triazole and 1,3,4-oxadiazole. The structural formulae of the synthesized compounds were elucidated in terms of elemental and spectroscopic analyses. All synthesized compounds were estimated by testing total antioxidant capacity, iron‐reducing power, the scavenging activity against ABTS and DPPH radicals in addition to testing anti‐diabetic, anti‐Alzheimer and anti‐arthritic activities. All compounds displayed good to potent bioactivity. Compounds 6, 10 exhibit the highest antioxidant and free radicals scavenging activities. Furthermore, compounds 6, 10 demonstrate the strongest inhibition of α‐amylase and α-glucosidase. Compound 12 exhibit strongest acetylcholinesterase inhibition among prepared compounds. However, compounds 18a,b, 19 show a significantly higher inhibition percentage for protein denaturation and proteinase. The most bioactive prepared compounds 6, 10 and 12 were investigated toward docking methodology against appropriate protein.

In vitro and In Silico Molecular Modeling Studies of Newly Synthesized Pyrrole Derivatives for their Antimicrobial and Anticancer Properties

Background: Pyrroles are biologically active scaffolds that can have a number of different effects. They also have unique pharmacophores inside their ring system that make it easier to make molecules that are more active. Significantly, in the past ten years, research has been conducted on the anti-bacterial properties, with a particular emphasis on drug-resistant Gram-positive and Gram-negative pathogens such as mycobacteria. Additionally, scaffolds based on pyrroles were utilized in the production of anti-tumor medicines that function by modulating or suppressing genes. Objective: This research aimed to create new pyrrole derivatives by chemical means and evaluate their antimicrobial and anticancer properties. Methods: By reacting diverse 1H-pyrrole-2-carbohydrazide derivatives with benzaldehyde under normal conditions, a number of pyrrole variations were created. IR, mass spectroscopy, NMR, and elemental analysis were used to characterize the synthesized compounds. The serial dilution method was used to assess antimicrobial activity, along with a molecular docking study against the enzyme α-topoisomerase II (α-Topo II), which effectively controls the topology of DNA. This enzyme is strongly expressed in rapidly dividing cells and is crucial for transcription, replication, and chromosome structure. Pyrrole and its synthetic derivatives are known to exhibit strong anticancer activity by specifically targeting α-Topo II, which has led multiple researchers to investigate α-Topo II inhibitors as potential anticancer medicines. Consequently, designing pyrroline derivatives is interesting since the succinimide portion of the joined heteroaromatic molecule can selectively engage with the ATP binding pocket via the hydrogen bond network. Newer synthesized compounds were also docked via Schrodinger 2022-4 into the active pocket of the three-dimensional crystallographic structure of the ATP site of human topoisomerase IIα (htopo IIα) (PDB ID: 1zxm). Results: Among the newly synthesized pyrrole derivatives, compounds demonstrated significant anti- microbial activity. In addition, the AutoDock Vina application was used to perform in-silico docking computations. Compounds 1a and 1h were found to have a stronger antiproliferative effect than compounds against MCF-07 breast cancer cell linen our study, ligands 1a and 1b exhibited better binding energies of -5.049 and -5.035 kcal/mol, respectively. Most of the synthesized pyrrole derivatives showed promising antiproliferative effects; however, further in vivo investigations are needed to confirm or refute these results. Conclusion: The results of this investigation show that pyrrole derivatives have the potential to be effective antimicrobial and anticancer agents. While resolving safety issues, the structural alterations carried out in this study enhanced the compounds' medicinal capabilities. To clarify the underlying mechanisms of action and enhance the pharmacological characteristics of these new pyrrole derivatives, further research is necessary.

Exploring the Antitumor Potential of New Indazole-indolizines Designed by Molecular Hybridization

Background: Cancer represents the major health problem faced by the population of the world, remaining one of the main causes of death. Hence, the development of new targeted antitumor drugs with high efficacy and lower toxicity is still needed. Objective: As a continuation of our work to discover new molecules with cytotoxic properties, two heterocyclic scaffolds, namely indolizine, and indazole, were combined in the same molecule, aiming to improve the bioactivity. This article focused on the synthesis, characterization, and biological evaluation of a series of new indazole-indolizine hybrid compounds. Methods: The biological potential of the synthesized compound was investigated in vitro against the human farnesyltransferase enzyme and NCI 60 tumor cell lines panel. While the farnesyltransferase inhibitory activity was modest, a very good antiproliferative action was observed for compound 4a, which, at a concentration of 10 μM, inhibited the growth of 20 types of cancer cells by more than 50% and showed cytotoxic action against the ovarian cancer cell line OVCAR-4. Results: A series of novel indazole-indolizine hybrids were synthesized via a [3+2] cycloaddition reaction, fully characterized and biologically evaluated for antitumor potential. Conclusion: Compound 4a could be a promising starting point in the development of new antitumoral agents. Further biological investigations will be performed to identify the biological target of the compounds. Moreover, different synthetic strategies to introduce new substituents on the indolizine core will be addressed.

Pyrimidine appended heterocycles: synthesis, characterization, and biological evaluation

A new class of pyrimidine-based heterocycles has been successfully synthesized via a simple and efficient way starting from 2-keto-thiophene (1). The α,β-unsaturated ketone (chalcone) (3) was first synthesized by treating the ketone (1) with 4-methoxy benzaldehyde (2), followed by treating with amino formamidine hydrochloride to afford the intermediate pyrimidine moiety (4) which was converted to amide functionalized pyrimidines (5a–e), pyrimidine-2-imines (6a–e) and thiophene tethered pyrimidine-imidazoles (7a–e). The structures assigned to the new compounds are confirmed by IR, NMR, and MS studies. The newly synthesized compounds were subjected to a molecular docking study with the protein of Staphylococcus aureus (PDB ID: 1JIJ), for antioxidant and antibacterial activity. The compounds 5a, 6a, 6b, and 7d were found to show hydrogen bond interaction with active site amino acid residues with the binding energy of −8,08, −8.39, −8.64, and −8.02 kJ/mol, respectively, and may act as potential inhibitors of bacterial tyrosyl-tRNA synthetases. The biological study envisioned that the synthesized compound 7b has shown potent antioxidant properties with 74.07% scavenging activity at 400 µg/mL and compound 6b was found to exhibit excellent antibacterial activity with 16, 20, 21, and 22 mm zone of inhibition against S. aureus, Escherichia coli, Salmonella paratyphi-A and Bacillus subtilis bacterial strains, respectively.

Trivalent oleanolic acid-glucose conjugates: Synthesis and efficacy against Influenza A virus

Influenza A virus (IAV) leads to significant morbidity and mortality due to the seasonal epidemics and spread. We have demonstrated that oleanolic acid (OA) C28 glucose conjugates and OA trimers are capable of effectively blocking the recognition and interaction between the influenza virus and host cells. In this study, a series of OA-glucose trimers were designed and synthesized through the CuAAC reaction. All trimers underwent screening for anti-IAV activities in vitro. Among these, compounds 13a and 13b showed inhibitory activity against the influenza virus, with IC50 values of 0.68 μM and 0.47 μM, respectively, demonstrating greater potency than oseltamivir (IC50 = 1.36 μM). Results from the time-of-addition experiment and hemagglutination inhibition assay suggest that these OA-glucose trimers may disrupt the recognition between the HA protein of IAV and sialic acid receptors on host cells, thus blocking viral entry. Furthermore, it was found that compound 13b effectively inhibits IAV infection in BALB/c mice. This study has elucidated the structure-activity relationships of OA trimers against the influenza virus and highlighted the utility of multivalent OA conjugates for enhancing ligand-target interactions in anti-influenza virus drug design, laying a groundwork for future research into the antiviral applications of these natural products.