Medicinal Chemistry最新文献

Introduction: SYK (Spleen Tyrosine Kinase) regulates immune response and is a promising target for cancer, sepsis, and allergy therapies. This study aims to create novel compounds that serve as alternative inhibitors for cancer treatments targeting SYK.

Methods: A thorough combination of machine learning (ML) and physics-based methods was employed to achieve these goals, encompassing de novo design, multitier molecular docking, absolute binding affinity computation, and molecular dynamics (MD) simulation.

Results: A total of 5576 novel molecules with key pharmacophoric features were generated using an ML-driven de novo approach against 21 diaminopyrimidine carboxamide analogs. Pharmacokinetic and toxicity evaluation assisted by the ML approach revealed that 4353 chemical entities fulfilled the acceptable pharmacokinetic and toxicity profiles. By screening through binding energy threshold from the physics-based multitier molecular docking, and ML-assisted absolute binding affinity identified the top four molecules such as RI809 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((2- aminocyclohexyl)oxy)benzamide), RI1393 (4-((2-aminocyclohexyl)amino)-2-(3-(1-methyl-1Hpyrazol- 5-yl)-4-(trifluoromethyl)benzyl)benzamide), RI2765 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((4- aminocyclohexyl)methyl)benzamide), and RI3543 (2-([1,1'-biphenyl]-2-ylmethyl)-4-(piperidin-3- yloxy)benzamide). The final molecules identified exhibit a strong affinity for SYK, attributed to their structural diversity and notable pharmacophoric characteristics. All-atom MD simulations showed that each final molecule retained significant binding interactions with SYK and stability in dynamic states, indicating their potential as anticancer agents. Calculated binding free energy for selected molecules using molecular mechanics with generalized Born and surface area (MMGBSA) ranged from -6 to -35 kcal/mol, indicating strong SYK affinity.

Conclusion: In conclusion, the integration of AI and physics-based methods successfully developed promising SYK inhibitors with significant potential. The molecules reported could be vital anticancer agents subjected to experimental validation.

Background: The approval of Sucrose Fatty Acid Esters (SFAEs) as food additives/ preservatives with antimicrobial potential has triggered enormous interest in discovering new biological applications. Accordingly, many researchers reported that SFAEs consist of various sugar moieties, and hydrophobic side chains are highly active against certain fungal species.

Objective: This study aimed to conduct aregioselective synthesis of SAFE and check the effect of chain length and site of acylation (i.e., C-6 vs. C-2, C-3, C-4, and long-chain vs. short-chain) on antimicrobial potency.

Methods: A direct acylation method maintaining several conditions was used for esterification. In vitro tests, molecular docking, and in silico studies were conducted using standard procedures.

Results: In vitro tests revealed that the fatty acid chain length in mannopyranoside esters significantly affects the antifungal activity, where C12 chains are more potent against Aspergillus species. In terms of acylation site, mannopyranoside esters with a C8 chain substituted at the C-6 position are more active in antifungal inhibition. Molecular docking also revealed that these mannopyranoside esters had comparatively better stable binding energy and hence better inhibition, with the fungal enzymes lanosterol 14-alpha-demethylase (3LD6), urate oxidase (1R51), and glucoamylase (1KUL) than the standard antifungal drug fluconazole. Additionally, the thermodynamic, orbital, drug-likeness, and safety profiles of these mannopyranoside esters were calculated and discussed, along with the Structure-Activity Relationships (SAR).

Conclusion: This study thus highlights the importance of the acylation site and lipid-like fatty acid chain length that govern the antimicrobial activity of mannopyranoside-based SFAE.

The conjugation of heterocyclic compounds often aims to leverage the beneficial properties of multiple compounds, which ultimately motivate the researchers to develop novel medicines with better efficacy, affinity, modified selectivity, dual/various modes of action, reduced side effects, lower cost, or enhanced therapeutic profiles. Hybrid molecules or conjugates for synergistic effect are obtained by combining structural features of two differently active fragments. Due to 1,3,4-oxadiazole's alternating single and double bonds, each atom providing a porbital perpendicular to the molecule's plane is stabilized like a drug molecule. The conjugate of 1,3,4-oxadiazole with piperazine moiety exhibits a range of physiological effects such as lowering blood pressure, antimicrobial, antitubercular, antioxidant, anticancer, antiproliferative, etc. Numerous natural molecules with pharmacological importance have also been found to possess conjugation between piperazine and 1,3,4-oxadiazole. As there is a lack of studies that focused on the synthetic protocols, pharmacological potential, and structure-activity relationship of the conjugates of 1,3,4-oxadiazoles and piperazines, the presented article highlights specifically these dimensions which have been reported in the last 10 years (2014-2024) These details assist researchers in designing their studies, and it is hoped that researchers from various scientific fields will find the manuscript beneficial for their future work on the conjugates of 1,3,4-oxadiazoles and piperazine.

Introduction: The marine habitat is a plentiful source of diverse, active compounds that are extensively utilised for their medicinal properties. Pharmaceutical trends have currently changed towards utilising a diverse range of goods derived from the marine environment.

Methods: This study aimed to examine the inhibitory effects of bioactive chemicals derived from marine algae and bacteria. The identification of these compounds was carried out through the process of Gas Chromatography-Mass Spectrometry (GC-MS) profiling. Subsequently, these compounds were subjected to docking simulations against a specific set of target proteins that are known to be frequently overexpressed in three distinct types of cancer.

Results: From the docking results, the ligand 1,4:3,6:5,7-Tribenzal-beta-mannoheptitol was found to be effective against the proteins mTOR (PDB ID: 4JSV) and FGFR2 (PDB ID:6V6Q). The findings of molecular simulation highlight that the investigated compound gets integrated with the target proteins effectively.

Conclusion: These marine derived compounds hold significant potential for further development and exploration in the field of cancer therapeutics.

Introduction: Breast cancer is the most common type of cancer among women. Steroidal or non-steroidal aromatase inhibitors (NSAIs) are used clinically, and in most cancer diseases, resistance is the most important problem.

Methods: The nitrogenous heterocyclic ring is noteworthy in the structure of non-steroidal aromatase inhibitors. This is the pharmacophore structure for aromatase inhibition. Because the enzyme interacts with the Fe²⁺ cation of the HEM structure in its active site, the most used agents in the clinic, such as anastrozole and letrozole, contain triazoles in their structures. Within the scope of this study, hybrid compounds containing both imidazole and triazole were synthesized.

Results: The synthesis was carried out by a 4-step reaction. The anticancer effects of the compounds were evaluated by MTT assay performed on A549 and MCF-7 cancer cells. Compound 4d showed anticancer activity against the MCF-7 cell line with IC₅₀=6.7342 uM value. This compound exhibited anticancer activity against the A549 cell line with an IC₅₀ = 17.1761 μM. In the MTT test performed on a healthy cell line to determine the cytotoxic effects of the compounds, the compound showed activity with a value of 4d IC₅₀=13.2088 uM. This indicates that the compound is not cytotoxic. Additionally, BrdU analysis was performed to evaluate whether the compound inhibits DNA synthesis. These selective effects of the compounds on breast cancer strengthened their aromatase enzyme inhibitor potential. For this reason, experiments conducted with both in vitro and in silico methods revealed a compound with high aromatase inhibitor potential.

Conclusion: The interactions observed as a result of molecular docking and dynamics studies are in harmony with activity studies. In particular, interactions with HEM600 demonstrate the activity potential of the compound.

Introduction: Cervical cancer is a global health problem due to its high incidence and prevalence in women, mainly in third-world countries. For the treatment of this disease, there are different therapeutic options, but these are not always effective, which gives rise to the search for new compounds using cheminformatics tools.

Objective: The objective of this study was to design, synthesize, and biologically evaluate N-(2- morpholinoethyl)-2-(naphthalen-2-yloxy)acetamide hydrochloride (1) and 2-(naphthalen-2-yloxy)- N-(2-(piperidin-1-yl)ethyl)acetamide hydrochloride (2) on the HeLa cell line in vitro. The referenced cell line from the American Type Culture Collection (ATCC^®CCL-2^™) was used, and the effect on cell viability was determined by MTT metabolic reduction-based assay at 24, 48, and 72 h.

Methods: Therapies directed at the σ1 receptor may be a treatment alternative since this receptor modulates the processes of cell proliferation and angiogenesis, producing cytoprotective or cytotoxic actions depending on the ligand with which it is coupled.

Results: The analysis showed that compounds 1 and 2 presented activity on HeLa cancer cells and viability at micromolar concentrations (1.923 μmol/mL and 0.374 μmol/mL, respectively). Moreover, the effect was maintained for 72 h.

Conclusion: Naphthaleneacetamide derivatives exhibited an inhibitory effect on the HeLa cell line, and the OSIRIS program predicted less toxicity than cisplatin.

Objective: The objective of this study is to explore the therapeutic potential of phytochemicals in cancer cell metabolism by investigating their ability to inhibit key molecular targets involved in tumor growth and drug resistance.

Methods: We evaluated specific phytochemicals against critical cancer-related targets such as GLS1, CKα, MGLL, IDH1, PDHK1, and PHGDH. Molecular docking methods were used to understand the binding interactions between phytochemicals and their selected targets. ADME (absorption, distribution, metabolism, and excretion) analysis and molecular dynamics (MD) simulations were conducted to assess pharmacokinetic properties and ligand-protein interaction dynamics, respectively. MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) calculations were utilized to estimate binding free energies.

Results: Molecular dynamics simulations demonstrate that phytochemicals like EGCG, Diosgenin, Withaferin A, and Celastrol exhibit stable binding to their respective targets, suggesting potential therapeutic benefits. Specifically, EGCG shows strong and non-toxic binding affinity with GLS1, making it a promising candidate for cancer treatment.

Conclusion: Our study underscores the potential of phytochemicals as effective inhibitors of cancer cell metabolism. The stable binding interactions highlight promising avenues for developing innovative cancer therapies. Further experimental investigations are warranted to validate these findings and advance the development of hybrid phytochemical-based treatments for combating chemoresistance.

Introduction: Nowadays, use of phosphate modifications in oligonucleotide backbone has become a common approach for imbuing its structure with the desired beneficial properties. The recent advances in successful application of different classes of phosphate modifications in the design of therapeutic oligonucleotides have led to a renewed interest in the development of approaches for introducing diverse classes of phosphate modifications.

Methods: This study aims to investigate the efficiency and optimize protocols for the application of the iodine-amine oxidation reaction to produce various N-alkyl phosphoramidate oligonucleotide derivatives during the conventional solid-phase phosphoramidite synthesis method.

Results: Various solvents and drying reagents were tested, and it was evaluated that even minor traces of water in a reaction mixture had a significant impact on yield. Using set of commercially available amines, it was shown that steric accessibility is a more critical parameter than nucleophilicity of the amino group in oxidative amination reaction. It was demonstrated that through use of amino alcohols and diamines during iodine-amine oxidation step various branched oligonucleotide structures can be synthesized.

Conclusion: The obtained data indicates that the oxidative amination approach can be a promising tool for preparing various oligonucleotide derivatives during solid-phase synthesis without the use of specialized phosphoramidite monomers.

Introduction: Cholinesterase enzymes play a pivotal role in hydrolyzing acetylcholine, a neurotransmitter crucial for memory and cognition, into its components, acetic acid, and choline. A primary approach in addressing Alzheimer's disease symptoms is by inhibiting the action of these enzymes.

Methods: With this context, our study embarked on a mission to pinpoint potential Cholinesterase (ChE) inhibitors using a comprehensive computational methodology. A total of 49 phytoconstituents derived from Cannabis sativa L underwent in silico screening via molecular docking, pharmacokinetic and pharmacotoxicological analysis, to evaluate their ability to inhibit cholinesterase enzymes. Out of these, two specific compounds, namely tetrahydrocannabivarin and Δ-9- tetrahydrocannabinol, belonging to cannabinoids, stood out as prospective therapeutic agents against Alzheimer's due to their potential as cholinesterase inhibitors. These candidates showcased commendable binding affinities with the cholinesterase enzymes, highlighting their interaction with essential enzymatic residues.

Results: They were predicted to exhibit greater binding affinities than Rivastigmine and Galantamine. Their ADMET assessments further classified them as viable oral pharmaceutical drugs. They are not expected to induce any mutagenic or hepatotoxic effects and cannot produce skin sensitization. In addition, these phytoconstituents are predicted to be BBB permeable and can reach the central nervous system (CNS) and exert their therapeutic effects. To delve deeper, we explored molecular dynamics (MD) simulations to examine the stability of the complex formed between the best candidate (Δ-9-tetrahydrocannabinol) and the target proteins under simulated biological conditions. The MD study affirmed that the ligand-ChE recognition is a spontaneous reaction leading to stable complexes.

Conclusion: Our research outcomes provide valuable insights, offering a clear direction for the pharmaceutical sector in the pursuit of effective anti-Alzheimer treatments.

The emergence of multidrug-resistant microbial strains poses a significant challenge to global public health. In response, researchers have been exploring innovative antimicrobial agents with enhanced efficacy and novel mechanisms of action. One promising approach involves the synthesis of hybrid molecules combining azetidinone and azole moieties, capitalizing on the respective antimicrobial properties of both structural elements. Natural and synthetic azetidinone derivatives hold a prominent position among medicinally significant compounds due to their varied and potent antibiotic activities. Interest persists in discovering new synthetic methods and refining existing ones, as well as applying these methods to create novel, biologically active azetidinone derivatives. Additionally, azoles are highly regarded in pharmaceuticals for their broad efficacy, tolerability, and oral availability. By merging these two pharmacophores, researchers aim to create compounds with synergistic or additive antimicrobial effects, potentially overcoming existing resistance mechanisms. Various synthetic strategies, including click chemistry and multicomponent reactions, have been employed to prepare these hybrid molecules efficiently. The antimicrobial potential of azetidinone-azole conjugates has been extensively evaluated against a spectrum of pathogens, including bacteria, fungi, and protozoa. These studies have demonstrated promising results, with several compounds exhibiting potent activity against both Gram-positive and Gramnegative bacteria, as well as clinically relevant fungal strains. Furthermore, SAR studies have provided valuable insights into the key structural features governing the antimicrobial properties of these conjugates, facilitating further optimization and rational design. In conclusion, the development of azetidinone-azole hybrids represents a promising avenue in the quest for novel antimicrobial agents. This study presents a comprehensive overview of recent advancements in synthesis and antimicrobial evaluation of azetidinone-azole conjugates.