Medicinal Chemistry最新文献

Background: 1,3,4-oxadizole and pyrazole derivatives are very important scaffolds for medicinal chemistry. A literature survey revealed that they possess a wide spectrum of biological activities including anti-inflammatory and antitumor effects.

Objectives: To describe the synthesis and evaluation of two classes of new niflumic acid (NF) derivatives, the 1,3,4-oxadizole derivatives (compounds 3 and (4A-E) and pyrazole derivatives (compounds 5 and 6), as EGFR tyrosine kinase inhibitors in silico and in vitro.

Methods: The designed compounds were synthesized using conventional organic synthesis methods. The antitumor activities of the new NF derivatives against HepG2 hepatocellular carcinoma and A549 non-small cell lung cancer cell lines were assessed in vitro via MTT assay, flow cytometry, RT-PCR, as well as via molecular docking studies.

Results: The cytotoxicity results indicated that the newly synthesized NF derivatives were cytotoxic against the two cancer cell lines, with compound 6 being the most cytotoxic, achieving the lowest IC₅₀ concentration. Furthermore, compound 6 targeted EGFR tyrosine kinase leading to cell cycle arrest at the G2/M cell cycle phase and induction of apoptosis. The in vitro biological investigation results matched those of the molecular docking analysis. In conclusion, the new NF derivatives, specifically compound 6, exhibited favorable pharmacokinetic features and are promising EGFR tyrosine kinase inhibitors.

Conclusion: A series of niflumic acid derivatives (3, 4A-E, 5, and 6) were successfully created, and FT-IR, ^{1H, ₁₃CNMR, and HRMS were used to confirm their chemical structures. According to molecular docking studies, compounds 3, 5, and 6 have the highest docking scores (ΔG), and most tested compounds have a good pharmacokinetic profile. Results of compound 6 in vitro antitumor activities showed that it is a promising EGFR tyrosine kinase inhibitor.}

Introduction: Breast cancer is the most common cancer affecting women worldwide,including Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer,which is developed due to the over-production of estrogen (the main hormone in breast cancer).

Method: The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as atarget for the treatment of breast cancer. During the current study, biochemical, computational, andSTD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3-butene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 µM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 =0.0147 ± 1.45 µM), anastrozole (IC50 = 0.0094 ± 0.91 µM), and exemestane (IC50 = 0.2 ± 0.032 µM).Kinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively.

Result: Docking studies on all active compounds indicated their binding adjacent to the heme groupand interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme.

Conclusion: STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to benon-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified newaromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research.

GPCR superfamily, the largest known family of membrane receptors, consists of six classes from A to F. GPR18 and GPR55, δ-branch of A class, had been reported to have no confirmed endogenous ligand and were named as "orphan receptors". Previous studies suggest that both GPR18 and GPR55 are possibly related to the migration and proliferation of cancer cells, macrophages and other inflammation-associated immune cells. Thus, they may be potential targets for inflammation, cancer and analgesia therapy. In this paper, we aimed to summarize the chemical structures and bioactivities of the agonists and antagonists of GPR18 and GPR55; moreover, we have briefly discussed the challenges and future perspectives in this field. This review will be beneficial for further design and synthesis of efficient agonists and antagonists towards GPR18 and GPR55- related disease treatment.

Berberine (BBR) is a quaternary ammonium alkaloid isolated from the Traditional Chinese Medicine Coptis chinensis. It possesses a plethora of pharmacological activities because its unique structure properties make it readily interact with macromolecules through π-π stacking and electrostatic interaction. Its anti-tumor effects are receiving more and more attention in recent years. Cytotoxicity and anti-proliferation are the important anti-tumor modes of BBR, which have been studied by many research groups. This study aims to review the structural modifications of BBR and its cytotoxic derivatives. Also, to study the corresponding structure-activity relationship. BBR showed potential activities toward tumor cells, however, its modest activity and poor physicochemical properties hindered its application in clinical. Structural modification is a common and effective approach to improve BBR's cytotoxic or anti-proliferative activities. The structural modifications of BBR, the cytotoxic or anti-proliferative activities of its derivatives, and the corresponding structure-activity relationship (SAR) were summarized in the review. The concluded SAR of BBR derivatives with their cytotoxic or anti-proliferative activities will provide great prospects for the future anti-tumor drug design with BBR as the lead compound.

Quinoline and its analogues are found in various natural products, many of which are active pharmacophores with significant bioactivities. This article discussed the plethora of quinoline derivatives and their analogues that have anti-cancer properties. The review will be helpful for the scientific community since several possible anticancer drugs based on quinolines are discussed here. In addition to this, the synthetic aspect of many such quinoline derivatives showing anti-cancer activities is also revealed in this article. These quinoline-based anti-oncogenic molecules can be synthesized using several acids, bases, and azides or with the help of reagents like Jone's reagent and Lawesson's reagent.

Calixarenes have always captured the attention of several researchers. They have the ability to entrap multiple molecules and form inclusion complexes with drugs due to their unique structure. Due to this property, they are being widely used in the development of several classes of drugs, most notably anticancer drugs. This review attempted to summarize the potential applications of calixarenes and its derivatives in the development of anticancer drugs, with a focus on the delivery of drug classes such as DNA intercalators, taxanes, DNA alkylators, and topoisomerase inhibitors. Calixarene-based macromolecular chemistry could therefore have a high potential for overcoming the toxicity of cancer chemotherapy and achieving targeted drug delivery.

Background: Diabetes mellitus is a metabolic disease that causes multiple complications and common comorbidities, which decreases the quality of life for people affected by the disease. Sodium glucose cotransporter type 2 (SGLT2) participates in the reabsorption of 90% of glucose in the kidneys; therefore, it is an attractive drug target for controlling blood glucose levels.

Objective: The aim in this work was to obtain new potential SGLT2 inhibitors.

Methods: A ligand-based virtual screening (LBVS) from the ZINC15, PubChem and ChemSpider databases using the maximum common substructure (MCS) scaffold was performed.

Result: A total of 341 compounds were obtained and analyzed by molecular docking on the active site of SGLT2. Subsequently, 15 compounds were selected for molecular dynamics (MD) simulation analysis. The compounds derived of spiroketal Sa1, Sa4, and Sa9 (≤ 3.5 Å) in complex with the receptor SGLT2 showed good stability during 120 ns of MD.

Conclusion: These compounds are proposed as potential SGLT2 inhibitors.

Background: A limited number of small molecules against SARS-CoV-2 has been discovered since the epidemic commenced in November 2019. The conventional medicinal chemistry approach demands more than a decade of the year of laborious research and development and a substantial financial commitment, which is not achievable in the face of the current epidemic.

Objective: This study aims to discover and recognize the most effective and promising small molecules by interacting SARS-CoV-2 M^pro target through computational screening of 39 phytochemicals from five different Ayurvedic medicinal plants.

Methods: The phytochemicals were downloaded from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) PubChem, and the SARS-CoV-2 protein (PDB ID: 6LU7; M^pro) was taken from the PDB. The molecular interactions, binding energy, and ADMET properties were analyzed.

Results: The binding affinities were studied using a structure-based drug design of molecular docking, divulging 21 molecules possessing greater to equal affinity towards the target than the reference standard. Molecular docking analysis identified 13 phytochemicals, sennoside-B (-9.5 kcal/mol), isotrilobine (-9.4 kcal/mol), trilobine (-9.0 kcal/mol), serratagenic acid (-8.1 kcal/mol), fistulin (-8.0 kcal/mol), friedelin (-7.9 kcal/mol), oleanolic acid (-7.9 kcal/mol), uncinatone (-7.8 kcal/mol), 3,4-di- O-caffeoylquinic acid (-7.4 kcal/mol), clemaphenol A (-7.3 kcal/mol), pectolinarigenin (-7.2 kcal/mol), leucocyanidin (-7.2 kcal/mol), and 28-acetyl botulin (-7.2 kcal/mol) from ayurvedic medicinal plants phytochemicals possess greater affinity than the reference standard Molnupiravir (-7.0 kcal/mol) against SARS-CoV-2-M^pro.

Conclusion: Two molecules, namely sennoside-B, and isotrilobine with low binding energies, were predicted as most promising. Furthermore, we carried out molecular dynamics simulations for the sennoside-B protein complexes based on the docking score. ADMET properties prediction confirmed that the selected docked phytochemicals were optimal. These compounds can be investigated further and utilized as a parent core molecule to create novel lead molecules for preventing COVID-19.

Aims: To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation.

Background: Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms.

Objective: Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxazolyl- and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides.

Methods: Thirteen trifluoromethylisoxazolyl- and thirteen trifluoromethylpyrazolyl-substituted (hetero) aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by ¹H and ¹³C NMR as well as element analysis. The obtained compounds were evaluated, using the CA esterase activity assay, for their potential to block the catalytic activity of bovine CA (bCA).

Results: Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide.

Conclusion: Coupling the bCA esterase activity assay with thermal shift assay represents a streamlined and economical strategy for the prioritization of sulfonamide CA inhibitors for subsequent evaluation in vivo.