Medicinal Chemistry最新文献

The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area, relative structural rigidity, and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility, oral bioavailability, and ADME characteristics, as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review, we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure-activity relationship concerning different biological activities of various piperazine-containing drugs was also highlighted to provide a good understanding to researchers for future research on piperazines.

The worldwide impact of cancer is further compounded by the constraints of current anticancer medications, which frequently exhibit a lack of selectivity, raise safety apprehensions, result in significant adverse reactions, and encounter resistance mechanisms. The current situation highlights the pressing need to develop novel and more precise anticancer agents that prioritize safety and target specificity. Remarkably, more than 85% of drugs with physiological activity contain heterocyclic structures or at least one heteroatom. Nitrogen-containing heterocycles hold a significant position among these compounds, emerging as the most prevalent framework within the realm of heterocyclic chemistry. This article explores the medicinal chemistry behind these molecules, highlighting their potential as game-changing possibilities for anticancer medication development. The analysis highlights the inherent structural variety in nitrogen-containing heterocycles, revealing their potential to be customized for creating personalized anticancer medications. It also emphasizes the importance of computational techniques and studies on the relationships between structure and activity, providing a road map for rational medication design and optimization. Nitrogen- containing heterocycles are a promising new area of study in the fight against cancer, and this review summarises the state of the field so far. By utilizing their inherent characteristics and exploiting cooperative scientific investigations, these heterocyclic substances exhibit potential at the forefront of pioneering therapeutic approaches in combating the multifaceted obstacles posed by cancer.

Background: In the last years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused more than 760 million infections and 6.9 million deaths. Currently, remains a public health problem with limited pharmacological treatments. Among the virus drug targets, the SARS-CoV-2 spike protein attracts the development of new anti-SARS-CoV-2 agents.

Objective: The aim of this work was to identify new compounds derived from natural products (BIOFACQUIM and Selleckchem databases) as potential inhibitors of the spike receptor binding domain (RBD)-ACE2 binding complex.

Methods: Molecular docking, molecular dynamics simulations, and ADME-Tox analysis were performed to screen and select the potential inhibitors. ELISA-based enzyme assay was done to confirm our predictive model.

Results: Twenty compounds were identified as potential binders of RBD of the spike protein. In vitro assay showed compound B-8 caused 48% inhibition at 50 μM, and their binding pattern exhibited interactions via hydrogen bonds with the key amino acid residues present on the RBD.

Conclusion: Compound B-8 can be used as a scaffold to develop new and more efficient antiviral drugs.

Background: Vascular endothelial growth factor receptor-2 (VEGFR-2) is a critical protein involved in tumor progression, making it an attractive target for cancer therapy.

Objective: This study aimed to synthesize and evaluate novel thieno[2,3-d]pyrimidine analogues as potential anticancer VEGFR-2 inhibitors.

Methods: The thieno[2,3-d]pyrimidine analogues were synthesized following the pharmacophoric features of VEGFR-2 inhibitors. The anticancer potential was assessed against PC3 and HepG2 cell lines. The VEGFR-2 inhibition was evaluated through IC₅₀ determination. Cell cycle analysis and apoptosis assays were performed to elucidate the mechanisms of action. Molecular docking, molecular dynamics simulations, MM-GBSA, and PLIP studies were conducted to investigate the binding affinities and interactions with VEGFR-2. Additionally, in silico ADMET studies were performed.

Results: Compound 8b demonstrated significant anti-proliferative activities with IC₅₀ values of 16.35 μM and 8.24 μM against PC3 and HepG2 cell lines, respectively, surpassing sorafenib and exhibiting enhanced selectivity indices. Furthermore, compound 8b showed an IC₅₀ value of 73 nM for VEGFR-2 inhibition. Cell cycle analysis revealed G2-M phase arrest, while apoptosis assays demonstrated increased apoptosis in HepG2 cells. Molecular docking and dynamic simulations confirmed the binding affinity and interaction of compound 8b with VEGFR-2, supported by MMGBSA and PLIP studies. In silico ADMET studies indicated the drug development potential of the synthesized thieno[2,3-d]pyrimidines.

Conclusion: The study highlights compound 8b as a promising VEGFR-2 inhibitor with potent anti-proliferative activities. Its mechanism of action involves cell cycle arrest and induction of apoptosis. Further, molecular docking and dynamic simulations support the strong binding affinity of compound 8b to VEGFR-2.

Introduction: Drug resistance to existing antimicrobial drugs has become a serious threat to human health, which highlights the need to develop new antimicrobial agents.

Methods: In this study, a new set of 3-hydroxypyridine-4-one derivatives (6a-j) was synthesized, and the antimicrobial effects of these derivatives were evaluated against a variety of microorganisms using the microdilution method. The antimicrobial evaluation indicated that compound 6c, with an electron-donating group -OCH₃ at the meta position of the phenyl ring, was the most active compound against S. aureus and E. coli species with an MIC value of 32 μg/mL. Compound 6c was more potent than ampicillin as a reference drug.

Results: The in vitro antifungal results showed that the studied derivatives had moderate effects (MIC = 128-512 μg/mL) against C. albicans and A. niger species. The molecular modeling studies revealed the possible mechanism and suitable interactions of these derivatives with the target protein.

Conclusion: The obtained biological results offer valuable insights into the design of more effective antimicrobial agents.

This study aims to provide a thorough analysis of nitrogen-containing heterocycles, focusing on their therapeutic implications for the development of targeted and effective antiviral drugs. To better understand how nitrogen-containing heterocycles can be used to create antiviral drugs, this review adopts a systematic literature review strategy to compile and analyze pertinent research studies. It combines information from various fields to understand better the compounds' mode of action and their therapeutic potential. This review paper summarizes data from multiple sources to highlight the promising potential of heterocycles containing nitrogen as promising possibilities for future antiviral treatments. The capacity to engage selectively and modulate critical pathways bodes well for their use in developing new viral therapies. In conclusion, nitrogen-containing heterocycles are shown to be of utmost importance in the field of medicinal chemistry, as emphasized by the review paper. It emphasizes the central importance of chemical insights and pharmacological potential in developing novel and effective antiviral medicines by bringing them together.

Background: Tuberculosis has been the main cause of mortality of infectious diseases worldwide, with strongly limited therapeutic options. With increasing resistance and missing suitable drugs in those cases, there is a strong need for novel antituberculostatic drugs. We developed novel N-aryl 1,4-dihydropyridines with various substitution patterns to evaluate them as antituberculostatic agents.

Methods: 1,4-Dihydropyridine derivatives were synthesized and purified by column chromatography or recrystallization. The mycobacterial growth inhibition was determined in a fluorescent mycobacterial growth assay.

Results: The compounds were prepared in a simple one-pot reaction under acidic conditions with structurally varied components. The substituent effects on the determined mycobacterial growth inhibitory properties are discussed.

Conclusion: Lipophilic diester substituted derivatives show promising activities that were additionally affected by the aromatic substituent functions. Thus, we identified compounds with activities almost reaching that of the used antimycobacterial drug as control.

Background: Hepatitis C is an inflammatory condition of the liver caused by the hepatitis C virus, exhibiting acute and chronic manifestations with severity ranging from mild to severe and lifelong illnesses leading to liver cirrhosis and cancer. According to the World Health Organization's global estimates, a population of about 58 million have chronic hepatitis C virus infection, with around 1.5 million new infections occurring every year.

Objective: The present study aimed to identify novel molecules targeting the Hepatitis C viral RNA Dependent RNA polymerases, which play a crucial role in genome replication, mRNA synthesis, etc. Methods: Structure-based virtual screening of chemical libraries of small molecules was done using AutoDock/Vina. The top-ranking pose for every ligand was complexed with the protein and used for further protein-ligand interaction analysis using the Protein-ligand interaction Profiler. Molecules from virtual screening were further assessed using the pkCSM web server. The proteinligand interactions were further subjected to molecular dynamics simulation studies to establish dynamic stability.

Results: Molecular docking-based virtual screening of the database of small molecules, followed by screening based on pharmacokinetic and toxicity parameters, yielded eight probable RNA Dependent RNA polymerase inhibitors. The docking scores for the proposed candidates ranged from - 8.04 to -9.10 kcal/mol. The potential stability of the ligands bound to the target protein was demonstrated by molecular dynamics simulation studies.

Conclusion: Data from exhaustive computational studies proposed eight molecules as potential anti-viral candidates, targeting Hepatitis C viral RNA Dependent RNA polymerases, which can be further evaluated for their biological potential.

Background: Heparins are sulfated glycosaminoglycans that are used as anticoagulants to treat thrombosis. Heparins exhibit other potential therapeutic effects, such as anti-inflammatory, anti-viral, and anti-malarial effects. However, the strong anticoagulant activity of heparins poses a risk of life-threatening bleeding, limiting their therapeutic use for other diseases beyond thrombosis. To exploit the other effects of heparins and eliminate the bleeding risk, we explored an alternative polymer called lignosulfonic acid sodium (LSAS), which acts as a sulfonated heparin mimetic. LSAS targets factor XIa to exert an anticoagulant effect, and thus, unlike heparins, it is unlikely to cause bleeding.

Methods: This study investigated the multiple effects of LSAS to identify potential leads for complex pathologies treatment. A series of chromogenic substrate hydrolysis assays were used to evaluate the inhibition of three inflammation-related proteases by LSAS. Its chemical antioxidant activity against the system of ABTS/hydrogen peroxide/metmyoglobin was also determined. Lastly, the effect of LSAS on TNFα-induced activation of the NF-κB pathway in HEK-293 cells was also tested to determine its cellular anti-inflammatory activity.

Results: The results showed that LSAS effectively inhibited human neutrophil elastase, cathepsin G, and plasmin, with IC₅₀ values ranging from 0.73 to 212.5 μg/mL. Additionally, LSAS demonstrated a significant chemical antioxidant effect, with an IC50 value of 44.1 μg/mL. Furthermore, at a concentration of approximately 530 μg/mL, LSAS inhibited the TNFα-induced activation of the NF-κB pathway in HEK-293 cells, indicating a substantial anti-inflammatory effect. An essential advantage of LSAS is its high water solubility and virtual non-toxicity, making it a safe and readily available polymer.

Conclusion: Based on these findings, LSAS is put forward as a polymeric heparin mimetic with multiple functions, serving as a potential platform for developing novel therapeutics to treat complex pathologies.

Background: Over-expression of Vascular Endothelial Growth Factor Receptors (VEGFRs) leads to the hyperactivation of oncogenes. For inhibition of this hyperactivation, the USA Food Drug Administration (FDA) has approved many drugs that show adverse effects, such as hypertension, hypothyroidism, etc. There is a need to discover potent natural compounds that show minimal side effects. In the present study, we have taken structurally diverse known VEGFR2 inhibitors to develop a Quantitative Structure-Activity Relationship (QSAR) model and used this model to predict the inhibitory activity of natural compounds for VEGFR2.

Methods: The QSAR model was developed through the forward stepwise Multiple Linear Regression (MLR) method. A developed QSAR model was used to predict the inhibitory activity of natural compounds. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessment and molecular docking studies were performed. The binding stability of the natural compounds with VEGFR2 was elucidated through Molecular Dynamics (MD) simulation.

Results: The developed QSAR model against VEGFR2 showed the regression coefficient of the training dataset (r²) as 0.81 and the external regression coefficient of the test dataset (r2 test) 0.71. Descriptors, viz., electro-topological state of potential hydrogen bonds (maxHBint2, nHBint6), atom types (minssNH), maximum topological distance matrix (SpMAD_Dt), and 2D autocorrelation (ATSC7v), have been identified. Using this model, 14 natural compounds have been selected that have shown inhibitory activity for VEGFR2, of which six natural compounds have been found to possess a strong binding affinity with VEGFR2. In MD simulation, four complexes have shown binding stability up to 50ns.

Conclusion: The developed QSAR model has identified 5 conserved activity-inducing physiochemical properties, which have been found to be correlated with the anticancer activity of the nonidentical ligand molecules bound with the VEGFR2 kinase. Lavendustin_A, 3'-O-acetylhamaudol, and arctigenin have been obtained as possible lead natural compounds against the VEGFR2 kinase.