Compounds 3a Research Articles

The chalcone scaffold pyrazole is important in organic and medicinal chemistry. This study presents the design and synthesis of new chalcone-coupled pyrazole derivatives (1a-1o). The new compounds were characterized using FT-IR, 1H-NMR, 13C-NMR, GC-MS, elemental analysis, and cytotoxic analysis on MCF-7 and HepG2 cancer cell lines. The synthesized compounds also underwent molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and DFT (density functional theory) studies. Compound 1a showed high cytotoxic activity against MCF-7 cells (LC50, 0.62 ± 0.01 µM), outperforming standard Doxorubicin. Compounds were examined using molecular docking, ADME-T, and DFT calculations. Compound 1a had a higher binding affinity (-10.8 Kcal/mol) than Doxorubicin (-4.7 Kcal/mol). ADME-T profile and pharmacokinetic predictions were performed on the analogs. DFT with the B3LYP/6-311++G (DP) basis set helped determine optimal shape and dimensions. Additional Gaussian 16-based DFT calculations were conducted on compounds (1a-1o). The HOMO-LUMO analysis revealed compound 1a had a significant energy gap (2.5056 eV, from -7.94026 eV to -5.43465 eV). Compound 1a may be a promising anti-cancer agent.

Novel heterocyclic analogs with dual antibacterial and anticancer potential were synthesized to address the limitations posed by multidrug resistance and current therapies. A series of N-heterocyclic peptoids was synthesized using the Ugi-multicomponent reaction. The obtained derivatives were evaluated for their antibacterial activity toward S. aureus and E. coli, as well as for their anticancer potential against A549 lung adenocarcinoma cells. Cytotoxic effects on Vero cells were also assessed. Furthermore, molecular docking and molecular dynamics simulations were performed to investigate the binding affinities and interaction stabilities of the compounds with target proteins. Compound 5d exhibited pronounced antibacterial activity against both bacterial strains. Furthermore, compounds 5k and 5l showed significant anticancer efficacy with minimal cytotoxic effects on normal cells. Molecular docking studies indicated strong binding affinities for compounds 5a, 5d and 5l, while molecular dynamics simulations confirmed the stability of the corresponding ligand-protein interactions. The Ugi-derived peptoids exhibited potent antibacterial and anticancer activities, suggesting that their structural framework offers valuable insights for future structure-activity relationship studies and the design of novel therapeutic derivatives.

Histone deacetylases (HDACs) play a crucial role in gene expression, and their dysregulation is linked to various cancers. HDAC inhibitors, particularly hydroxamic acid derivatives, have shown promising anticancer effects, with several approved for clinical use. This research aimed to synthesize novel 7-hydroxycoumarin-based N-hydroxyamides, evaluate their HDAC inhibition, and assess their in vitro cytotoxic effects. The structures of the synthesized compounds were established by analysis of their physicochemical, elemental, and spectroscopic data. HDAC, in vitro assays, and molecular docking were performed using standard procedures. The biological results showed that compounds 5d, 5e, 5j, 5l, and 7k exhibited potential cytotoxicity toward all five cancer cell lines. These compounds displayed potent cytotoxicity against the NCCIT cancer cell line with IC50 values of 4.53-1.45 μM. However, they exhibited weak to medium HDAC inhibitory activity with IC50 values ranging from 21.72 to 4.79 μM. Docking simulation studies with selected compounds revealed that compounds 5a and 7k formed stable interactions in the active site of HDAC enzyme with binding affinities ranging from -7.43 to -7.103 kcal/mol, respectively. The study revealed several compounds with potential HDAC inhibitory activity and cytotoxicity. However, they were still less effective in inhibiting HDACs than SAHA and Trichostatin A. Their reduced potency may be related to the length of the linker linked to the surface recognition group. This provides important insight into the future design of hydroxamic acids of this type. The research results suggest that some hydroxamic acids (5a and 7k) warrant further evaluation, and these results could serve as a basis for designing more potent HDAC inhibitors and antitumor agents.

Design, synthesis, and biological evaluation of chalcone derivatives as selective Monoamine Oxidase-B inhibitors with potential neuroprotective effects.

Design, synthesis, and antitumor evaluation of new pyridazinone scaffolds as dual EGFR/VEGFR-2 kinase inhibitors and apoptotic cells inducers.

Eight thiadiazole-thiophene hybrids 4, 5, 6, and 7 were prepared by incorporating a thiophene ring system into the precursor 2-(cyanomethyl)-1,3,4-thiadiazole compounds 3a and 3b, through different strategic methods. The structures of these hybrids were elucidated using spectral techniques (IR, NMR, and Mass spectrometry). The DFT (B3LYP) modeling of the built hybrids revealed comparable non-planar configurations and HOMO-LUMO composition, covering the full skeleton (π- and π*-orbitals, respectively). The antimicrobial efficacies of the produced analogues were appraised against both Gram (+ve) and (-ve) bacterial pathogens. Analogues 5a, 5b, 6a, and 7b revealed potent activity (MIC 3.125-6.25 μg/mL). Meanwhile, these analogues established moderate to good inhibitory efficiency of DNA gyrase (IC₅₀ = 4.46 ± 0.09-8.38 ± 0.33 μM), where the analogue 5a exhibited the highest activity, very close to the novobiocin (reference drug; IC₅₀ = 4.01 ± 0.03 μM). Moreover, the molecular docking with a target protein PDB: 6FQM has been performed to discover the interaction patterns of synthesized hybrids. Hybrids 5a, 5b, and 4b showed significant binding energies and stable interaction profiles. Furthermore, the investigated hybrids were evaluated for their pharmacokinetic and drug-likeness properties using SwissADME predictions, where compounds 3a and 3b are the most promising drug-like leads among the thiadiazole hybrids.

Cancer is one of the most complex diseases. Its multidrug resistance and poor prognosis make the development of antitumor drugs still a difficult task. 18β-glycyrrhetinic acid (18β-GA) has shown great potential for tumor prevention and treatment. However, inherent defects, such as low bioavailability, limit its use. Herein, based on a molecular hybridization strategy, two series of α, β-unsaturated carbonyl modified 18β-GA derivatives were synthesized using 18β-GA as the parent nucleus. Among them, compounds 9a, 9g and 9i exhibited the strongest antiproliferative activity, with IC50 values ranging from 1.52 to 3.46 μM against HCT-116, SH-SY5Y and HepG2 cells. The key target of the three active derivatives was predicted to be human STAT3 through reverse target finding. Docking analysis proved that all three derivatives showed strong binding affinity to STAT3 in silico, suggesting potential as STAT3 inhibitors.

In the current study, new pyrazolo [1,5-a]pyrimidine-3-carbonitriles were synthesized and evaluated for their inhibitory activity against Pim-1 kinase. The most potent inhibitors were 4d, 5d, and 9a with IC50 values (0.61, 0.54 and 0.68 μM) compared to quercetin (IC50 = 0.91 μM), with some selectivity towards Pim-1 and Pim-3 over Pim-2. Compound 4d exhibited a 1.5-fold increased cytotoxic activity compared to doxorubicin against the MCF-7 cell line, whereas compound 9a showed an analogous activity to doxorubicin. Furthermore, compounds 4d, 5d, and 9a arrested the cell cycle at G2-M phase with a decrease in the G1-phase population. Compounds 4d, 5d, and 9a induced apoptosis in MCF-7 cells by a 94-, 64-, and 78-fold increase in the entire apoptotic and necrotic cells compared to the untreated control cells and increased the levels of wild p53 in MCF-7 cells by 6.5, 6, and 5.7-fold indicating that these compounds may induce apoptosis via increasing the expression level of p53. Moreover, a promising safety profile was shown for compound 4d on MCF-10A normal breast cells. Besides, docking of the desired compounds into Pim-1 ATP binding site showed a noteworthy binding mode for the enzyme inhibition. Additionally, a 2D QSAR identified the potential structural features controlling the Pim-1 inhibitory activity attained via the targeted pyrazolo[1,5-a]pyrimidines.

Structure-based design of benzofuran library as P. aeruginosa quorum sensing inhibitors: Synthesis, biological evaluation and molecular docking study.

Design, synthesis and structure-activity relationship of 5'-prenylated chalcone derivatives inhibited the proliferation of human non-small cell lung cancer cells via inducing ferroptosis.

Synthesis of 6-ethoxyphenyl 4-fluorobenzenesulfonate-tagged thiosemicarbazones as carbonic anhydrase inhibitors: In-vitro and in silico approach.

Discovery and structure-activity relationship study of novel hydantoin-based inhibitors targeting mutant isocitrate dehydrogenase 1 (mIDH1).

Epilepsy encompasses numerous syndromes characterized by spontaneous, intermittent, and abnormal electrical activity in the brain. Affecting about 1-2% of the population, it is estimated that approximately 30-40% of patients experience refractory epilepsy, which does not respond to traditional anticonvulsant drugs. Therefore, developing novel, safe, and effective antiepileptic drugs remains a medical need. In this study, we synthesized a series of isoindoline-1,3-dione derivatives and evaluated their anticonvulsant effects. Compounds (2a-j) and (5) were obtained with yields ranging from 52-97%. These compounds were assessed for their protective effects on the following parameters: a) time to first seizure (seizure latency), b) seizure duration, and c) mortality rate post-seizure. The most active compound, (2a), increased seizure latency, reduced seizure duration, and lowered the mortality rate. These findings indicate that compound (2a) is a promising new anticonvulsant prototype, offering an alternative to current anticonvulsant drugs.

Fluorescent binding assay for allosteric ligands of liver pyruvate kinase.

Enhanced detection of pesticides: evaluating monocarbamoylcarboxylic acids modified with amines for glyphosate and dicamba sensitivity.

The boron-vertices of o-carborane have long been considered to be inert in conjugation with π-substituents. Herein, we demonstrate that the boron vertices of o-carborane can be engineered to participate in intense charge-transfer (CT) transitions. Through strategic design-appending electron-donating carbazoles at the boron vertices-we synthesized three 9,12-substituted o-carboranes (1, 2a, and 2b). While 1 only shows LE emission, compounds 2a and 2b, which contain phenyl groups at the carbon vertices, show unprecedented dual emission with a colossal gap of up to 505nm (2.1eV) between bands. Photophysical and theoretical studies reveal that photoexcitation triggers a unidirectional conversion from a locally excited (LE) state to a CT state, yielding the first direct evidence of CT from a boron-functionalized donor into the carborane cage. This CT emission is highly sensitive to environment, exhibiting aggregation-induced emission enhancement with quantum yields reaching 80%. Our findings disrupt the longstanding carbon-centric view of carborane-based luminescence, unveiling a new strategy to activate boron-vertex participation in electronic conjugation, opening a pathway for the development of high-performance dual-emissive materials based on o-carborane.

Abstract A simple base‐mediated one‐pot synthetic green methodology has been successfully employed for the synthesis of 1,3‐diphenylpyrazole‐based spirooxindolo‐1,2,4‐oxadiazole derivatives. The newly synthesized analogues were tested for their in vitro anti‐tubercular activity (anti‐TB) against Mycobacterium tuberculosis H37Rv strain, and the results were reported as minimum inhibitory concentration (MIC) values ranging from 3.125 to 25 µg/mL. Especially, the five compounds 3a, 3f, 3k, 3q , and 3v exhibited good to moderate anti‐TB activity with MIC of 3.125 µg/mL when compared to the reference drug ethambutol (MIC: 1.56 µg/mL). In silico Molecular docking and molecular dynamics simulations of the protein–ligand complex ( 3a , 3f, 3k , and 3v ) against Mycobacterium tuberculosis DprE1 (PDB ID: 5OEQ) of M. tuberculosis H37Rv strain revealed that these four compounds could be promising anti‐mycobacterial candidates, as evident from the binding results and stability of the docked–ligand complexes with considerable least binding energies. ADME parameters were also studied to assess the drug likeness, which clearly shows that the newly developed compounds might be useful for the future development of novel anti‐tubercular drugs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications for the treatment of inflammation, pain, and fever, primarily acting as competitive inhibitors of the cyclooxygenase (COX) enzymes. The present study aimed to design a series of trifluoromethyl-pyrazole-carboxamide derivatives as potential NSAID candidates, with a focus on achieving selective COX-2 inhibition and reduced cytotoxicity. In addition, their potential anticancer effects and pharmacokinetic properties were evaluated through in vitro and in silico analyses. The coupling reaction of aniline derivatives and pyrazole-carboxylic acid was used to synthesize a series of trifluoromethyl-pyrazole-carboxamide derivatives. Initially, the newly synthesized compounds were characterized using FTIR, HRMS, 1H-NMR, 13C-NMR, and MicroED techniques. Their inhibitory activities and potential selectivity against the key isoenzymes COX-1 and COX-2 were evaluated in vitro using a COX inhibition assay kit. Furthermore, the cytotoxicity of these compounds was assessed using an MTS assay against human normal cell lines (HEK293T) and hepatic cell lines (LX-2), as well as molecular docking and ADMET analyses were conducted. Based on the biological evaluation, compound 3b exhibited the most potent inhibitory activity against the COX-1 enzyme, with an IC₅₀ value of 0.46 µM. Additionally, it demonstrated notable COX-2 inhibitory activity, with an IC₅₀ value of 3.82 µM. In contrast, compound 3g showed the highest selectivity ratio for COX-2 (1.68), alongside potent COX-2 inhibition (IC₅₀ = 2.65 µM), outperforming the reference drug ketoprofen, which displayed a selectivity ratio of 0.21 and an IC₅₀ value against COX-2 of 0.164 µM. Furthermore, compound 3d exhibited strong COX-2 selectivity (selectivity ratio = 1.14) with an IC₅₀ value of 4.92 µM. All synthesized compounds demonstrated negligible cytotoxic effects against the tested normal cell lines. However, compound 3a exhibited cytotoxic activity against CaCo-2, MCF-7, Hep3B and HepG2 cancer cell lines with IC50 range 43.01-58.04 µM. Molecular docking studies revealed the formation of favorable interaction profiles within the respective binding sites, which were comparable to those of the control agent ketoprofen, supporting the potent in vitro inhibitory activities observed. Pharmacokinetic analysis of the newly synthesized compounds indicated favorable properties regarding absorption, distribution, metabolism, excretion, and toxicity (ADMET), confirming the drug-like profiles of these chemical structures. Consequently, these agents are highly recommended for further investigation in clinical studies. Compounds 3b, 3d, and 3g demonstrated potent COX inhibition with notable COX-2 selectivity, supporting their promise as leads for safer anti-inflammatory drug development. Additionally, compound 3a displayed moderate cytotoxic effects against several cancer cell lines, suggesting possible dual anti-inflammatory and anticancer potential. Overall, the favorable drug-like properties and low toxicity profiles justify further preclinical investigation of these pyrazole-carboxamide derivatives.

Abstract The synthesis of imidazo[1,2‐ b ]isoquinolin‐3‐amine derivatives was accomplished by an AlCl 3 ‐catalyzed Groebke–Blackburn–Bienaymé (GBB) reaction, showing a direct and effective method for producing diverse heterocycles. A library of compounds (4a–4j) was synthesized by a multicomponent reaction involving isoquinolin‐3‐amine, aromatic aldehydes, and tert ‐butyl isocyanide in methanol at mild reaction conditions. The catalytic effects of different Lewis and Brønsted acids were analysed, with AlCl 3 proving to be the most efficient, with yields of up to 84%. Structural characterization was carried out by various spectroscopic methods (IR, NMR, and MS). The synthesized compounds were evaluated for their cyclooxygenase (COX) inhibitory activity, with compound 4a (4‐F) exhibiting the highest COX‐II selectivity (IC 50 = 1.14 ± 1.01 µM, SI = 15.0), followed by compound 4i (3‐Br, 5‐Cl) with an IC 50 of 1.01 ± 0.12 µM and SI = 13.2, surpassing celecoxib. Molecular modeling studies validated the binding interactions inside the COX‐I and COX‐II active sites, reinforcing their potential as anti‐inflammatory drugs.

Abstract The synthesis of a new family of pyrazole–imidazole hybrid compounds 3a – 3f is reported. These compounds were obtained in one step through an equimolar condensation of pyrazole and imidazole derivatives. The corresponding structures were confirmed by 1 H and 13 C NMR spectroscopy, as well as high‐resolution mass spectrometry (HRMS). The antidiabetic potency of these compounds was evaluated by determining their activities to inhibit the α‐amylase enzyme. Compound 3d showed an IC 50 value of 1.5 × 10 −3 mg/mL, which was lower than that of the used positive control acarbose. Molecular docking calculations were also carried out, and the obtained data corroborate with the experimental findings.