Future medicinal chemistry最新文献

Aim: This study aimed to design, synthesize, and evaluate a hybrid chalcone-pyrazoline derivatives as potential anticancer agents targeting B-Raf kinase in lung cancer.

Material & methods: Chalcone-pyrazoline derivatives (PY1-PY10) were synthesized via Claisen-Schmidt condensation followed by cyclization, characterized using FT-IR, NMR, and LC-MS. In vitro cytotoxic activity was assessed against A549 human lung cancer cells using the MTT assay. Molecular docking studies were performed with B-Raf kinase (PDB ID: 2FB8) using Schrödinger software. ADME properties were predicted using SwissADME.

Result: Compound PY7 exhibited the most potent cytotoxicity (IC₅₀ = 6.45 µM) and the highest docking score (-8.89 kcal/mol), showing strong binding interactions with GLN530 in B-Raf kinase. Structure Activity Relationship analysis revealed that electron-withdrawing para-nitro substituents enhanced potency, while electron-donating groups generally reduced activity. ADME profiling confirmed all compounds complied with Lipinski's Rule of Five, had high gastrointestinal absorption, and displayed favorable drug-likeness.

Conclusion: The findings identify PY7 as a promising lead candidate with potent anticancer activity, strong B-Raf binding affinity, and favorable pharmacokinetics. This work supports chalcone-pyrazole scaffolds as viable templates for the development of novel targeted lung cancer therapeutics.

Aim: To synthesize and evaluate the anticancer potential and mechanism of a naturally occurring compound, chrysin derivatives.

Materials & methods: A series of 7-substituted phenyl pyrano derivatives of chrysin (3a-k) were synthesized by Michael-type addition reaction and their structures were elucidated using spectroscopic techniques, such as FT-IR, H¹ NMR, C¹³ NMR, and MS. In vitro anticancer and cytotoxicity effects were evaluated using MCF7 and mesenchymal stem cells (MSCs). Apoptosis mechanism was evaluated through the expression of pro- and anti-apoptotic proteins, for instance, Bax, Bcl-2, p53, and p21, and the binding score and stability was computed using AutoDock Vina and GROMACS. In silico ADMET analysis was performed via web-based tools like Swiss ADME, pkCSM, ADMETlab 2.0, PreADMET, ProTox II, and Molinspiration.

Results: Structure activity relationship (SAR) analysis revealed that the 4-hydroxy substituted phenyl derivative (3h) is important for anticancer activity. 3 h enhanced the expression of Bax, Bcl-2, and p53 while decreases in the expression of oncogene p21 at 16.5 µM concentration showed superior activity to standard carboplatin and was found safe up to 77.95 μM. All the derivatives displayed favorable pharmacokinetic and drug-like properties.

Conclusion: The 4-hydroxy substituted phenyl derivative (3h) spectacled enhanced anticancer and safety profile along with considerable pharmacokinetic parameters.

Aim: To develop potent B cell lymphoma 6 (BCL6) inhibitors, novel N-phenyl-4-pyrimidine-diamine analogs were designed and synthesized via structure-based and computer-aided drug design.

Methods: Starting from the hit compound ZB979, we synthesized three series of pyrimidinediamine BCL6 inhibitors (13a-13e, 14a-14c and 15a-15g) and evaluated their inhibitory activities on BCL6-SMRT interaction using homogeneous time-resolved fluorescence (HTRF) assays. The most promising candidate, compound 15d, was further assessed for its anti-proliferative activity and modulation of BCL6 downstream target genes, suppression of germinal center (GC) formation.

Results: Compound 15d demonstrated significant BCL6-SMRT inhibition with favorable physicochemical properties (Calculated LogP (ClogP) and topological polar surface area (tPSA)).

Conclusion: These findings highlight the potential of pyrimidinediamine-based scaffolds as novel BCL6 inhibitors, warranting further structural optimization to improve their efficacy.

Poly(ADP-ribose) polymerase (PARP) plays a key role in DNA damage repair and has become a critical target for tumor therapy. In recent years, several PARP inhibitors, such as Olaparib and Niraparib, have achieved clinical success in breast cancer susceptibility genes (BRCA) mutant tumors by exploiting the synthetic lethality of homologous recombination-deficient cancers. However, problems have emerged in clinical application, such as hematologic toxicity, which may be related to the lack of subtype selectivity of PARP-1/-2. Selective inhibitors of PARP-1 that can overcome toxicity have emerged as a new strategy for PARP inhibitor development. In this review, we first reveal the conformational heterogeneity of the PARP-1/-2 active region through homology comparison and systematically explain the spatial topological characteristics of its selective binding pockets. Then, the structure-activity relationships of 14 reported selective inhibitors of PARP-1 are analyzed to reveal the key pharmacophores occupying the active region, as well as to characterize the specific groups bound to the selective binding domain. Finally, we discuss the structural requirements of selective PARP-1 inhibitors and propose the "secondary site contact" design strategy for the development of new PARP inhibitors.

Aim: Searching for novel epidermal growth factor receptor (EGFR) inhibitors, 1-substituted 3,5-diphenyl pyrazolines 4a-i, 5a-i, 6a, and 6b bearing the terminal piperidine or morpholine moieties commonly observed in clinically approved EGFR inhibitors were synthesized as novel anti-cancer agents acting via EGFR inhibition.

Materials & methods: A series of 3,5-diphenyl pyrazolines was synthesized and screened for in vitro anti-cancer activity against 60 NCI cell lines.

Results: Pyrazolines 5d and 6a revealed broad-spectrum cytotoxic activities and potent EGFR inhibition with IC₅₀ values of 2.30 µM and 1.47 µM, respectively, in comparison to Vandetanib (IC₅₀ = 0.5 µM) and Gefitinib (IC₅₀ = 0.04 µM). Interestingly, compound 6a demonstrated a promising cytotoxic activity against the leukemia cell line (HL-60) and safety toward the normal cell line HSF. Additionally, compound 6a up-regulated proapoptotic markers and down-regulated Bcl-2 as an antiapoptotic marker in HL-60 cells. Docking simulations explained the EGFR inhibitory actions of 5d and 6a compared to Gefitinib. According to predictive models of oral bioavailability and drug-likeness, pyrazolines 5d and 6a are expected to be bioavailable and drug-like compounds.

Conclusion: Pyrazolines 5d and 6a are novel EGFR inhibitors with a broad-spectrum anti-cancer activity, and 6a has off-target antileukemic effect.

Introduction: Visceral leishmaniasis is a life-threatening infectious disease caused by the intracellular protozoan Leishmania, where interactions between the parasite and the host's intracellular components play a crucial role in tracking the incursion of infection. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) plays a critical role in regulating inflammation and eliciting a defensive immune response to the pathogen. Consequently, we aimed to explore the role of a desmuramylpeptide (NOD2 agonist) in visceral leishmaniaisis caused by Leishmania donovani.

Methodology: In this study, wedescribe the multistep solution-phase synthesis of a potent desmuramylpeptide (Compound 6) derived from trans-ferulic acid. This compound was subsequently evaluated for its in vitro biological activities against Leishmania donovani.

Results: Compound 6 demonstrated potent in vitro activity against L. donovani parasites (promastigote and amastigote forms) leading to successful clearance of parasites. Furthermore, it exhibited immunostimulatory effects by enhancing reactive oxygen species and nitric oxide production while showing moderate cytotoxicity against RAW 264.7 macrophages and HeLa cells. Notably, Compound 6 was more effective than muramyl dipeptide in promoting parasite clearance and eliciting robust immunomodulatory response.

Conclusion: Overall, the study highlights NOD2 as a critical mediator of immune modulation during Leishmania infection, suggesting its potential as a pharmacological target for host-directed immune intervention.

Aims: To design, synthesize, and evaluate pyrrolidine-based hybrids bearing indole, thiourea, and vinyl sulfone pharmacophores as dual inhibitors of human carbonic anhydrase I/II (hCAI/II) and acetylcholinesterase (AChE), with secondary profiling of complementary bioactivities.

Materials & methods: Three hybrids (6a, 6b, 8) were obtained via imine azomethine ylide 1,3-dipolar cycloaddition and derivatization. Structures were confirmed spectroscopically and assayed in vitro for hCAI/II and AChE inhibition. Additional evaluations included antioxidant (DPPH), antibacterial, antifungal, antituberculosis (M. tuberculosis H37Rv), cytotoxicity (HCT116, DPSCs), anti-inflammatory (COX-2, SOD1 ELISA, mouse xylene-induced), antidepressant (forced swim test), molecular docking, and in silico ADMET.

Results: Compound 6b was the most potent inhibitor (hCAII Ki 75.79 ± 2.83 nM, AChE Ki 43.17 ± 10.44 nM), outperforming acetazolamide (Ki 299.33 ± 45.44 nM) and tacrine (Ki 103.47 ± 11.54 nM). Compound 6a showed the strongest antioxidant effect (72.30% DPPH), antibacterial activity against A. baumannii (MIC 125 µg/ml, comparable to ampicillin), and superior anti-TB potency (MIC 31.25 µg/ml). Compound 6b exhibited stronger antibacterial activity (MIC 62.5 µg/ml). Both reduced COX-2 levels, and 6a increased SOD1. The hybrids were selectively cytotoxic to HCT116, sparing DPSCs. Docking studies confirmed key binding interactions, while ADMET predicted favorable profiles.     .

Conclusions: The hybrids validate a focused dual-target strategy. Compound 6b is the most potent hCAII and AChE inhibitor, while 6a emerges as a broader multi-target lead with antioxidant, antimicrobial, anti-inflammatory, and antidepressant potential.

Aim: Naja oxiana venom-induced alkaline phosphatase (ALP) enzyme has been documented for its detrimental effects post envenomation in the victims. Therefore, the present study was designed to evaluate the effectiveness of 4-aminobenzenesulfonamide-based derivatives against cobra venom-induced ALP enzyme.

Methods: Targeted derivatives were synthesized and characterized via FTIR, ¹H NMR, and ¹³C NMR followed by docking targeted protein techniques. Furthermore, synthetic analogues were evaluated in vitro for their potential to halt ALP activity.

Results: Among all the synthetic compounds, (SB-5) showed remarkably potent inhibitory activity against the targeted enzyme (94%, IC₅₀, 3.25 µM, p < 0.001). Furthermore, kinetic studies revealed that (SB-5) acts as a mixed-type inhibitor of ALP enzyme. Its Ki value (13.19 µM) indicated a high binding affinity, accompanied by a favorable safety profile - characterized by high gastrointestinal (GI) absorption, compliance with Lipinski's Rule of Five (0 violations), and a low likelihood of crossing the blood-brain barrier, suggesting good oral bioavailability. The Ramachandran plot offered further insight into the positioning of amino acid residues within the most favored regions, thereby reinforcing the potential to inhibit ALP activity.

Conclusion: The present study confirms the effectiveness of 4-aminobenzenesulfonamide-based derivative (SB-5) as a promising inhibitor of ALP and as a lead candidate for future drug development.

Human mitochondrial ClpP (hClpP), a pivotal protease regulating mitochondrial protein homeostasis, has emerged as an important target for anticancer drug development. In recent years, significant progress has been made in designing small molecules targeting hClpP, primarily classified into activators and inhibitors. Activators specifically stimulate ClpP proteolytic activity by mimicking the mechanism of its chaperone protein ClpX, with representative compounds, such as imipridone derivatives (ONC201/206/212) and their optimized products (ZK53, 7k, etc.) demonstrating excellent antitumor efficacy. Investigation of their structural design and pharmacological properties provides theoretical insights for subsequent drug development. Significant progress has been made in agonist research, and although there are still issues that need to be addressed, hClpP-targeted drugs hold promise as new therapies for the treatment of cancer.