Med Chem [JOURNAL]
Sun
200 papers
Pluripotent Cinnamic Acid and Valproic Acid Hybrid Molecules Designed as Strong Anti-inflammatory and Anti-hyperlipidemic Compounds.
Theodosis-Nobelos P, Rekka EA
Med Chem · 2025 Sep · PMID 40908693 · Publisher ↗
INTRODUCTION: Inflammation and oxidative stress are considered main pathophysiological factors for neuronal and cardiovascular diseases, also leading to the impairment of main cellular metabolic pathways. Promotion of hy...
INTRODUCTION: Inflammation and oxidative stress are considered main pathophysiological factors for neuronal and cardiovascular diseases, also leading to the impairment of main cellular metabolic pathways. Promotion of hyperlipidemia is also the result of inflammatory and oxidative (ROS production) processes. Additionally, compounds of medicinal interest like valproic and caffeic acids and amino acids like proline and tyrosine have shown antiinflammatory and cellular protective potency. METHODS: In the present study, amides of L-tyrosine, L-proline, and L-cysteine, and an ester of cinnamyl alcohol were synthesized by conjugation with caffeic acid, valproic acid, or (E)-3- (3,4-dimethoxyphenyl)acrylic acid (cinnamic acid derivative). This design aimed to explore the multiple activities of novel compounds, via the combination of structures related to the desired biological characteristics. The synthesized compounds were tested for their effects on oxidative stress in vitro and on acute inflammation and hyperlipidemia in vivo. RESULTS: The synthesized compounds decreased carrageenan-induced rat paw oedema up to 69% (the most active compound 6), and 49% for compound 2, an amide of valproic acid with L-tyrosine. Several compounds were effective antioxidants, with radical scavenging and lipid peroxidation inhibitory activity. Additionally, the synthesized molecules significantly decreased the plasma lipidemic markers in tyloxapol-induced hyperlipidemic rats. They decreased plasma triglycerides and total cholesterol up to 53% and 78% (compound 1), and LDL-cholesterol up to 69% (compound 5). DISCUSSION: The anti-inflammatory activity of the derivatives was equal to or much higher than that of ibuprofen and tolfenamic acid, two widely applied NSAIDs (nonsteroidal antiinflammatory drugs), whilst compound 2 was 3.3 times more active than valproic acid, with the latter being tested at four times higher dose. Concerning the antioxidant activity, several compounds were comparable to the strong antioxidant Trolox, and the effect on cholesterol levels for all the derivatives was comparable to or equal to simvastatin [a 3-hydroxy-3-methylglutaryl (HMG) coenzyme A reductase inhibitor]. CONCLUSION: The multiple activities of the synthesized compounds may serve for the manipulation of conditions involving inflammation and lipid deregulation, or the further optimization and production of compounds towards these ailments.
Design, Synthesis, Biological Evaluation, and Studies of Tetrazole Derivatives as Potential Cytotoxic Agents.
Parepalli MCS, Galla R
Med Chem · 2025 Aug · PMID 40873173 · Publisher ↗
INTRODUCTION: Despite significant progress in cancer treatment, the need for new anticancer agents remains critical. Current research efforts are directed toward discovering novel compounds that exhibit potent cytotoxic...
INTRODUCTION: Despite significant progress in cancer treatment, the need for new anticancer agents remains critical. Current research efforts are directed toward discovering novel compounds that exhibit potent cytotoxic activity while minimizing adverse effects. Thus, tetrazole derivatives have gained attention due to their potential biological activities, including anticancer effects. METHODS: A series of tetrazole derivatives (6a-l) were synthesized via α-keto halogenation of 2,4-difluoroacetophenone, followed by cyclization, nucleophilic substitution, and subsequent coupling with various aryl carboxylic acids. The synthesized compounds were characterized using spectroscopic techniques, including C NMR, H NMR, FT-IR, and HRMS. Their cytotoxic potential was assessed through an MTT assay across four human cancer cell lines. Other cytotoxic evaluations included apoptosis induction, cell cycle analysis, and EGFR-TK inhibition assays. Additionally, molecular docking studies were conducted to explore binding interactions, and in silico ADME predictions were performed to assess pharmacokinetic properties. RESULTS: The results obtained by the MTT assay indicated that compound 6d demonstrated significant cytotoxicity against A549 (lung cancer) cell lines, with an IC50 value of 2.74 μM, compared to doxorubicin (IC = 3.87 μM). Furthermore, cell cycle analysis and apoptosis suggested that 6d arrested the cell cycle in the S phase and triggered apoptosis in A549 cells. Docking studies and EGFR-TK inhibition assay proposed that 6l had good binding affinity towards EGFR enzyme and acts as a potential inhibitor (IC 0.099 μM). The ADME analysis demonstrated favourable molecular properties, including acceptable lipophilicity, strong absorption, and high oral bioavailability. DISCUSSION: The synthesized tetrazole derivatives exhibited notable anticancer potential, with compound 6d inducing S-phase arrest and apoptosis in lung cancer cells, and 6l demonstrating strong EGFR inhibition. These biological effects were further supported by docking studies and favorable ADME profiles, providing mechanistic insight into their activity. CONCLUSION: These findings indicate that the synthesized derivatives offer a promising approach for developing innovative and effective cancer therapies.
Advances in Medicinal Chemistry of Fused and Substituted Piperazines: Unlocking their Potential as Anticancer Agents.
Singh S, Kumar R, Tripathi S … +2 more , Salahuddin, Mazumder A
Med Chem · 2025 Aug · PMID 40873172 · Publisher ↗
Cancer is an abnormal growth of normal cells and has become a global healthcare concern. The availability of safer anticancer drugs with exceptional selectivity for healthy cells and high efficacy against various forms o...
Cancer is an abnormal growth of normal cells and has become a global healthcare concern. The availability of safer anticancer drugs with exceptional selectivity for healthy cells and high efficacy against various forms of cancer remains a significant challenge. Therefore, there is a need to develop target-specific and safer anticancer drugs. In medicinal chemistry, heterocyclic compounds play a crucial role by exhibiting diverse biological activities. Specifically, nitrogen-containing heterocyclic compounds are widely studied due to their diverse activities. The piperazine moiety serves as the building block for several molecules and is reported to have the ability to inhibit the cell cycle (G1/S phase), suppress angiogenesis, and interact with DNA. Piperazine also exhibits a flexible binding feature that enables it to interact with a range of biological targets, making it effective against various types of cancer. As there is a continuous need for an anticancer drug with improved efficacy and fewer side effects, piperazine derivatives are attracting the attention of researchers. This review highlights recent methods for the synthesis of fused and substituted piperazines, their structure-activity relationships, and their interactions with biological targets or receptors as anticancer agents. Thus, the presented review will be helpful to medicinal chemists in designing anticancer molecules that incorporate piperazines.
Blueberries and Their Polyphenols: A Review of the Evidence and the Potential Impact on Inflammation, Oxidative Stress, Vascular and Cardiometabolic Function.
Sharma S
Med Chem · 2025 Jul · PMID 40734444 · Publisher ↗
Blueberries contain a wide range of bioactive compounds, including polyphenols- plant-based chemicals known for their antioxidant and anti-inflammatory properties. Numerous and animal studies have suggested that these c...
Blueberries contain a wide range of bioactive compounds, including polyphenols- plant-based chemicals known for their antioxidant and anti-inflammatory properties. Numerous and animal studies have suggested that these compounds may promote health. However, evidence regarding the effects of blueberries and their bioactive components in humans remains limited. This review focuses on 45 human studies investigating how blueberry consumption may influence markers of inflammation, oxidative stress, vascular function, cardiovascular health, and metabolic outcomes in both healthy and at-risk individuals. While some findings suggest potential benefits, especially for vascular function, more high-quality, well-controlled human trials are needed to confirm these effects. Furthermore, research exploring the relationship between the structure of specific polyphenols and their biological activity is essential for a deeper understanding of the mechanisms behind the reported health benefits.
Unlocking the Multifunctional Therapeutic Potential of Herbacetin: A Flavone derived Scaffold.
Tailor NK
Med Chem · 2025 Jul · PMID 40734443 · Publisher ↗
Herbacetin (HBT), a naturally occurring flavone, exhibits broad therapeutic -- potential, including anti-cancer, anti-inflammatory, antioxidant, antimicrobial, neuroprotective, and anti-diabetic effects, by modulating ke...
Herbacetin (HBT), a naturally occurring flavone, exhibits broad therapeutic -- potential, including anti-cancer, anti-inflammatory, antioxidant, antimicrobial, neuroprotective, and anti-diabetic effects, by modulating key signaling pathways such as NF-κB, PI3K/AKT, AP-1, SGK1/FoxO1, AMPK, SIRT1, MMP9, and NLRP3. It also inhibits several critical enzymes, including ornithine decarboxylase, ATP-citrate lyase, SGK1, AChE, α-glucosidase, and CYP3A4. In the context of cancer, HBT has shown particularly promising activity against breast cancer, liver carcinoma, human colon cancer, and epidermal carcinoma. Structurally, HBT shares significant similarity with well-known flavonoids such as quercetin and kaempferol, and the availability of established total synthetic methodologies makes it an attractive candidate for synthetic chemists. However, the structural modification and comprehensive evaluation of ' 'HBT's biological activity remain underexplored. This review highlights its isolation, total synthesis, pharmacological properties, molecular targets, and future directions, emphasizing the versatility of the HBT scaffold as a promising foundation for the development of novel therapeutic agents.
Chitosan-Based Materials: A Comprehensive Review on Anticancer Drug Development.
Tayeb FJ, Felemban MF, Ashour AA … +1 more , Shafie A
Med Chem · 2025 Jul · PMID 40698696 · Publisher ↗
Cancer remains one of the most formidable global health threats, responsible for millions of deaths annually due to the uncontrolled proliferation and spread of abnormal cells. The development of effective anticancer the...
Cancer remains one of the most formidable global health threats, responsible for millions of deaths annually due to the uncontrolled proliferation and spread of abnormal cells. The development of effective anticancer therapies is crucial, as anticancer drugs target key cellular mechanisms, including DNA replication, apoptosis, and essential signaling pathways. In this context, chitosan (CT) has emerged as a promising biomaterial for advancing cancer treatment. With its unique combination of biocompatibility, biodegradability, and versatility, CT is gaining significant attention as a platform for developing innovative drug delivery systems. Recent research has highlighted the potential of CT-based materials to enhance drug efficacy by enabling controlled release, improving bioavailability, and facilitating targeted tumor delivery. Further modifications to CT, such as carboxymethylation, sulfation, and graft copolymerization, have significantly expanded its application in cancer therapy, allowing for more efficient encapsulation of chemotherapeutic agents, reducing systemic toxicity, and combating multidrug resistance. This review focuses on the latest developments (2021-2024) in CT-based materials for anticancer drug delivery, exploring their design principles, therapeutic mechanisms, and clinical applications. Additionally, the review discusses the challenges faced in translating these promising systems to clinical practice and highlights future strategies for optimizing CT-based therapies to revolutionize cancer treatment.
Recent Advances in Molecular Docking Techniques: Transforming Perspectives in Distinct Drug Targeting and Drug Discovery Approaches.
Ansari RM, Mundke RN, Agrawal YO … +3 more , Goyal SN, Nakhate KT, Rathod SS
Med Chem · 2025 Jul · PMID 40696555 · Publisher ↗
INTRODUCTION: Drug targeting and drug discovery methodologies are advancing rapidly due to recent developments in molecular docking techniques. Molecular docking forecasts the interactions between a small molecule, such...
INTRODUCTION: Drug targeting and drug discovery methodologies are advancing rapidly due to recent developments in molecular docking techniques. Molecular docking forecasts the interactions between a small molecule, such as a potential medicine, and a target protein or receptor. OBJECTIVES: This comprehensive review focuses on significant advances in molecular docking algorithms such as Vina, Glide, and AutoDock, including their enhanced accuracy and efficiency in predicting drug-target interactions. It also examines how novel features, such as fragment-based docking, covalent docking, and virtual screening, have expanded the significance of docking in modern pharmaceutical research. METHODS: The literature search was carried out by employing search engines such as PubMed and Google Scholar with keywords such as Molecular Docking, Lead-Optimization, Protein Flexibility, Fragment-Based Docking, Covalent Docking, and Virtual Screening. RESULTS: This present state-of-the-art review highlights recent advances in various docking methodologies and their significant applications in drug discovery, while also discussing the scoring functions of some well-established studies. Furthermore, by predicting the interactions between putative medications and protein residues involved in the creation of covalent bonds, covalent docking provides new opportunities for targeting difficult drug-resistant mutations. The efficiency and precision of these simulations have been increased by improved sampling techniques and sophisticated algorithms, enabling the investigation of conformational changes and protein flexibility throughout the drug-binding process. CONCLUSION: These approaches may hasten the course of emerging new remedies, increase the precision of hit-finding, and make it easier to find cutting-edge treatments for a variety of diseases. Molecular docking alone is insufficient to ensure the safety and efficacy of a pharmacological agent for commercialization. While it predicts binding affinity and interaction, it does not account for pharmacokinetics, toxicity, off-target effects, or in vivo behavior. Therefore, experimental validation through MD simulation, ADMET, in vitro, in vivo, and clinical studies is essential.
Recent Advances in the Medicinal Chemistry of Cancer (Part II).
Yıldırım I
Med Chem · 2025 · PMID 40692148 · Publisher ↗
Abstract loading — click title to view on PubMed.
A Search for New Amidrazone Derivatives Containing 4-Oxybut-2-enoic Acid Moiety as Antibacterial Agents.
Paprocka R, Przybysz M, Pośpieszyńska K … +6 more , Chepkoech A, Jagleniec D, Godlewski A, Korczak K, Wiese-Szadkowska M, Kutkowska J
Med Chem · 2025 Jul · PMID 40671222 · Publisher ↗
INTRODUCTION: Bacterial diseases pose a significant challenge to modern medicine due to the rapid development of resistance by bacterial strains and the global migration of people, which facilitates the transmission of t...
INTRODUCTION: Bacterial diseases pose a significant challenge to modern medicine due to the rapid development of resistance by bacterial strains and the global migration of people, which facilitates the transmission of these diseases. Therefore, there is a need to develop new strategies to combat microorganisms and newer substances that could be used as antibiotics. METHODS: Six new derivatives, , containing a 4-oxybut-2-enoic acid moiety, were obtained by reacting amidrazones with maleic anhydride. The antimicrobial potency of compounds was studied using the microdilution method against the following bacterial strains: , and the fungal strain . Their antiproliferative activity was tested in cultures of human peripheral blood mononuclear cells stimulated with phytohemagglutinin. The bioavailability parameters of new compounds were predicted using Molinspiration software. RESULTS: Derivatives showed the strongest antibacterial activity, especially against and . Compounds inhibited the growth of . Compounds exhibited low antiproliferative activity towards human peripheral blood mononuclear cells. However, it is necessary to evaluate whether all compounds are well absorbed after oral administration. DISCUSSION: The most promising antibacterial activity was demonstrated by derivatives possessing a 2-pyridyl substituent at the R1 position () or a phenyl ring at the R position (2a, 2f). CONCLUSION: Compound demonstrated the highest antibacterial activity and selectivity in inhibiting the growth of . Additionally, it exhibited low toxicity to human lymphocytes and demonstrated favorable bioavailability parameters. Therefore, its structure can be used as a starting point for designing new antimicrobials, such as targeted therapies for yersiniosis, beyond traditional antibiotics.
Identification of Potential Dual HDAC6 and HSP90 Inhibitors for the Treatment of Cancer using Molecular Docking, Molecular Dynamics and MM/PBSA Studies: A Comprehensive Study.
Yucel MS, Akcok I
Med Chem · 2026 · PMID 40626544 · Publisher ↗
BACKGROUND: Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The...
BACKGROUND: Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of HDAC6 and Hsp90 can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers. OBJECTIVE: The objective of this study was to explore potential compounds that can inhibit both HDAC6 and Hsp90 proteins. METHODS: In this study, a number of in-silico computational techniques were employed. A total of 791 molecules, sharing at least 30% similarity with previously identified four HDAC inhibitors, were obtained from the ZINC15 database and subjected to docking on HDAC6 and Hsp90 proteins. The top eight ligands demonstrating the best binding scores against both targets, with panobinostat and ganetespib serving as reference compounds for HDAC6 and Hsp90, respectively, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands. RESULTS: A detailed molecular docking, molecular dynamics simulations and ADME studies have revealed that ZINC27653366 exhibited the highest inhibitory potential against both Hsp90 and HDAC6 target proteins, making it the most promising inhibitor. CONCLUSION: In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.
Antioxidant and Cytotoxic Activity of the Aporphine Alkaloid (Boldine) Against DMH-induced Colorectal Carcinogenesis in Wistar Rats: An , and study.
Kashyap MK, Ved A, Wal P … +1 more , Singh AP
Med Chem · 2025 Jul · PMID 40619663 · Publisher ↗
OBJECTIVE: The objective of this study is to investigate the role of the aporphine alkaloid boldine as a potential inhibitor of specific protein targets involved in colorectal cancer, using docking and molecular dynamic...
OBJECTIVE: The objective of this study is to investigate the role of the aporphine alkaloid boldine as a potential inhibitor of specific protein targets involved in colorectal cancer, using docking and molecular dynamics simulation studies, and to evaluate its therapeutic potential in modulating the pathological progression of colorectal cancer. In this study, we evaluated the antioxidant and cytotoxic effects of boldine using and methods. METHODS: The 2-dimensional structure of boldine was retrieved from the PubChem database. Its interactions with colorectal cancer target proteins were analyzed using structures obtained from the RCSB Protein Data Bank (https://www.rcsb.org/), which provides the crystal structures of tubulin (PDB ID: 1Z2B), human NF- κB (1A3Q), human interleukin-2 (1M47), and EGFR-kinase. Molecular docking was then performed using Schrödinger software. Molecular docking and molecular dynamics (MD) simulations were conducted to evaluate Boldine's binding affinity and stability with colorectal cancer protein targets. On the Growmac platform, we performed the molecular simulation, and the simulation was only done with the highest docking score. Additionally, molecular dynamics was performed for 100 ns. Boldine was added to the colorectal cancer cell line (HCT116) at different doses, and the cytotoxic effects of the treatment were evaluated using cell viability assays. Furthermore, Boldine's capacity to scavenge reactive oxygen species (ROS) and modify the oxidative stress assay was used to assess its antioxidant capability. Boldine's in vivo anticancer effectiveness was examined using DMH-induced colorectal cancer in Wistar Rats. After Boldine was administered (100mg/Kg), Tumour progression, histological alteration, and oxidative stress markers were evaluated. The study aimed to ascertain how boldine affects tumor growth in DMH-inducedDMH colorectal carcinogenesis. RESULTS: Molecular docking revealed favorable binding interactions between boldine and key targets implicated in colorectal cancer. The data supported the hypothesis that boldine modulates essential pathways associated with cancer development. Boldine exhibited a dose-dependent reduction in colorectal cancer cell viability, indicating potential cytotoxic effects. Furthermore, boldine demonstrated antioxidant properties by effectively scavenging reactive oxygen species (ROS) and modulating oxidative stress markers in vitro. In animal models, boldine administration resulted in a significant reduction in tumor growth. Histopathological examination revealed favorable changes in tumor morphology. Additionally, boldine demonstrated antioxidant effects in vivo by modulating oxidative stress markers. CONCLUSION: According to this extensive study performed , , and , boldine may be able to prevent CRC through its antioxidant and cytotoxic properties. These results encourage more research into boldine as a viable option for treating CRC. It is successfully done, and we can say that boldine is a valuable addition to the CRC treatment choice.
Syntheses and Identification of New Dithiophosphinic Acid Complexes and Their Potential as Photodynamic Agents in Cancer Therapy.
Coşkun KA, Bulat E, Yılmaz H … +4 more , Sağlam EG, Tutar L, Ur Rehman F, Tutar Y
Med Chem · 2025 Jul · PMID 40619662 · Publisher ↗
BACKGROUND: The photo-efficacy of oncological phototherapy for both internal and external tumors is encouraging. When light and photochemotherapeutic drugs are applied together, precise cancer targeting, minimal invasive...
BACKGROUND: The photo-efficacy of oncological phototherapy for both internal and external tumors is encouraging. When light and photochemotherapeutic drugs are applied together, precise cancer targeting, minimal invasiveness, and innovative modes of action are made possible. Current developments in photoactive compounds and new light sources are promising for further advancement. OBJECTIVE: When designing photosensitizers, metal complexes may be advantageous since the metal can enhance stability and photocytotoxicity while facilitating their localization and quantification. The absorption spectra of photosensitizers limit their excitation wavelengths, which impact light tissue penetration that differs in various organs. Since longer wavelength light penetrates deeper, PDT is typically carried out at wavelengths greater than 620 nm. Additionally, employing lower intensity (>4-8 J/cm) energy can greatly lessen the pain and discomfort induced by red-light PDT. METHODS: Low-level laser therapy exposure was used to assess the dithiophosphinic acid complexes' photodynamic treatment efficacy in MCF-7 cells. Following the administration of the complexes at concentrations within IC values, red light (4 J, 780 nm) was applied to the cells. Afterward, MCF-7 cells were cultured for 24 hours to evaluate the photodynamic effects of the compounds on cancer cells. Cell viability was assessed using the XTT assay kit. RESULTS: DTPA complexes have shown effectiveness as photodynamic agents in cancer therapy, with Ni(II) and Ni(II)-pyridine complexes demonstrating significant cytotoxicity against cancer cells. CONCLUSION: Light-activated cancer cell therapies are promising, and the synthesized complexes affect the cell cycle and apoptosis-regulating proteins. The compounds can be employed as anticancer agents and a fine starting template for photodynamic drug design.
Promising Flavone Derivatives as Anticancer Agents.
Patil VA, Thombre KR, Gupta KR … +1 more , Umekar MJ
Med Chem · 2025 Jul · PMID 40611409 · Publisher ↗
<p> Currently, the main focus of anticancer drug development and research is to develop anticancer treatment strategies that are both less harmful and more effective. Flavones, a subclass of flavonoids, have shown great...
<p> Currently, the main focus of anticancer drug development and research is to develop anticancer treatment strategies that are both less harmful and more effective. Flavones, a subclass of flavonoids, have shown great promise in the advancement of anticancer drugs because of their strong bioactive properties. Fruits, vegetables, and medicinal plants are abundant sources of these naturally occurring compounds, which have a variety of biological activities such as anti-inflammatory, anti-cancer, and antioxidant properties. Flavones and their derivatives have attracted a lot of attention recently because of their potential to modify significant molecular pathways that are involved in the growth, apoptosis, angiogenesis, and metastasis of cancer cells. The objective of this review is to present a thorough analysis of the chemical makeup of flavone as an anticancer agent. By altering the flavone scaffold's structure, there are beneficial chances to improve its therapeutic qualities, such as its potency, selectivity, and pharmacokinetics. The structural alterations of flavone derivatives that improve their anticancer potency and selectivity are highlighted. Most noteworthy, flavones offer a promising framework for the creation of new anticancer medications, and further research into them may help create more potent and focused cancer treatments.
Exploring the Cholinesterase Inhibitory Potential of Azines Bearing a 4,4-bisdimethylaminobenzophenone Scaffold: An Experimental and Computational Approach.
Ahad G, Alam A, Elhenawy AA … +7 more , Ahmad I, Ur Rahman F, Ur Rehman M, Ali A, AlAsmari AF, Alasmari F, Khan M
Med Chem · 2025 Jun · PMID 40598729 · Publisher ↗
BACKGROUND: Acetyl and butyrylcholinesterase are significant enzymes involved in neurological diseases, and the development of more effective inhibitors is crucial for beneficial interference. OBJECTIVE: To evaluate the...
BACKGROUND: Acetyl and butyrylcholinesterase are significant enzymes involved in neurological diseases, and the development of more effective inhibitors is crucial for beneficial interference. OBJECTIVE: To evaluate the cholinesterase inhibition effect of the synthetic bis-Schiff base compounds and discover the electronic properties as well as binding affinities through computational studies. METHODS: The compounds were synthesized and screened against acetyl and butyrylcholinesterase inhibitory activities in-vitro, while DFT analysis and molecular docking studies were performed for the product compounds. RESULTS: Seven compounds, including , and , exhibited excellent AChE activity, while nine compounds showed potent BChE inhibition compared to galantamine (IC50 = 156.4 ± 1.13 μM). Furthermore, the recent study on molecules 2a-e has provided valuable insights into their mechanism of action as inhibitors of the enzyme ChE, which is crucial for understanding how to regulate this enzyme's activity. Through the use of Time-Dependent Density Functional Theory (TD-DFT), the electronic characteristics of these molecules were meticulously examined, revealing that the Highest Occupied Molecular Orbitals (HOMO) are extensively delocalized across the molecular frameworks of the most active compounds. This suggests a significant degree of electron delocalization, which is often associated with chemical reactivity and stability. In comparison to standard galantamine, these compounds demonstrate a lower electrophilicity index, which is indicative of their increased biological efficacy and lower toxicity. CONCLUSION: These derivatives showed excellent AChE and BChE activities with favorable electronic properties and superior binding affinities, highlighting their potential as effective inhibitors as therapeutic agents.
Identification of Potential FDA-Approved Inhibitors of SARS-CoV-2 Helicase Through a Multistep Approach: A Promising Prospect for COVID-19 Treatment.
Eissa IH, Elkaeed EB, Elwan A … +2 more , Alsfouk AA, Metwaly AM
Med Chem · 2025 · PMID 40525420 · Publisher ↗
INTRODUCTION: In this research aiming at combating COVID-19, we employed advanced computer-based methods to identify potential inhibitors of SARS-CoV-2 helicase from a pool of 3009 clinical and FDA-approved drugs. METHOD...
INTRODUCTION: In this research aiming at combating COVID-19, we employed advanced computer-based methods to identify potential inhibitors of SARS-CoV-2 helicase from a pool of 3009 clinical and FDA-approved drugs. METHODS: To narrow down the candidates, we focused on VXG, the helicase's co-crystallized ligand, and sought compounds with chemical structures akin to VXG within the examined drugs. The initial phase of our study involved molecular fingerprinting in addition to structure similarity studies. RESULTS: Once the compounds most closely resembling VXG (29 compounds) were identified, we conducted various studies to investigate and validate the binding potential of these selected compounds to the protein's active site. The subsequent phase included molecular docking, molecular dynamic (MD) simulations, and MM-PBSA studies against the SARS-CoV-2 helicase (PDB ID: 5RMM). CONCLUSION: Based on our analyses, we identified nine compounds with promising potential as SARS-CoV-2 helicase inhibitors, namely aniracetam, aspirin, chromocarb, cinnamic acid, lawsone, loxoprofen, phenylglyoxylic acid, and antineoplaston A10. The findings of this research help the scientific community to further investigate these compounds, both and .
Exploring for Anti-Alzheimer Potential: An Extensive Computational Study including Molecular Docking, Molecular Dynamics, and ADMET Assessments.
Nour H, Yamari I, Abchir O … +4 more , Mounadi N, Samadi A, Belaidi S, Chtita S
Med Chem · 2025 · PMID 40525419 · Publisher ↗
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...
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 underwent 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.
Carbohydrates in Computational and Medicinal Chemistry.
Ozeki Y, Kawsar SMA
Med Chem · 2025 · PMID 40525418 · Publisher ↗
Abstract loading — click title to view on PubMed.
Optimized Strategies for the Synthesis and Structure-Activity Relationship of Imidazole as an Antiepileptic Drug.
Mangal S, Salahuddin, Mazumder A … +5 more , Kumar R, Rani S, Datt V, Ahsan MJ, Yar MS
Med Chem · 2025 Jun · PMID 40511647 · Publisher ↗
Imidazole is believed to be a highly multifunctional compound in the medicinal and biological sectors. This literature focuses on information about the synthesis and anticonvulsant activity presented by the imidazole nuc...
Imidazole is believed to be a highly multifunctional compound in the medicinal and biological sectors. This literature focuses on information about the synthesis and anticonvulsant activity presented by the imidazole nucleus. Epilepsy is a chronic brain disorder including multiple seizures and brain cell abnormalities. Due to its old and less effective treatment, with the increase in the number of patients suffering from epilepsy, researchers need to concentrate on the emergence of finding new treatments for epilepsy. Imidazole-containing analogs are found to be significant in the field of medicinal chemistry and the treatment for epilepsy. These studies prompted us to synthesize and provide insights into developing new imidazole-bearing antiepileptic drugs.
Novel Pyrrolopyrimidines as Inhibitors of CLK4 and HER2: Targeting Promising Anticancer Pathways.
Gries J, Totzke F, Hilgeroth A
Med Chem · 2026 · PMID 40464177 · Publisher ↗
INTRODUCTION: Dysregulated cellular signaling pathways involving protein kinases are critically implicated in cancer development. Consequently, protein kinases have emerged as key targets for novel anticancer therapies....
INTRODUCTION: Dysregulated cellular signaling pathways involving protein kinases are critically implicated in cancer development. Consequently, protein kinases have emerged as key targets for novel anticancer therapies. A range of kinase inhibitors, including small molecules and monoclonal antibodies, has been developed. Although early strategies focused on achieving high specificity to minimize adverse effects, resistance to these targeted therapies has limited their effectiveness. As a result, broader-spectrum inhibitors that act on multiple cancer-related kinases are now considered more promising therapeutic options. METHOD: We developed twenty-five new pyrrolopyrimidine derivatives featuring diverse substitution patterns to assess their potential as small-molecule inhibitors of the protein kinases CLK4 and HER2, both of which are significant therapeutic targets in metastatic breast cancer. Pyrrolopyrimidine derivatives were synthesized and purified by column chromatography. Their protein kinase inhibitory activity was evaluated through a radioactive ATP-competition assay. RESULTS: The compounds were obtained through a multi-step synthetic procedure, concluding with substitution reactions. The effects of different substituents on the inhibitory properties of the observed protein kinases are analyzed and discussed. DISCUSSION: Aniline-substituted derivatives exhibited the most potent activities, which were further modulated by N-substituted pyrroles. CONCLUSION: We identified both selective and dual inhibitors of the target kinases, demonstrating activity in the nanomolar range.
Potential Inhibitors of SARS-CoV-2 Developed through Machine Learning, Molecular Docking, and MD Simulation.
Khan A, Bhrdwaj A, Sharma K … +16 more , Arugonda R, Kaur N, Chaudhary R, Shaheen U, Panwar U, Natchimuthu V, Kumar A, Dey T, Panicker A, Prajapati L, Shainy NK, Sahila MM, Junior FJBM, Hussain T, Alrokayan S, Nayarisseri A
Med Chem · 2025 Jun · PMID 40464176 · Publisher ↗
BACKGROUND: The advent of Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19) pandemic, has impacted physical and mental health worldwide. The la...
BACKGROUND: The advent of Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19) pandemic, has impacted physical and mental health worldwide. The lack of effective antiviral drugs necessitates a robust therapeutic approach to develop anti-SARS-CoV-2 drugs. Various investigations have recognized ACE2 as the primary receptor of SARS-CoV-2, and this amalgamation of ACE2 with the spike protein of the coronavirus is paramount for viral entry into the host cells and inducing infection. Consequently, restricting the virus's accessibility to ACE2 offers an alternative therapeutic approach to averting this illness. OBJECTIVE: The study aimed to identify potent inhibitors with enhanced affinity for the ACE2 protein and validate their stability and efficacy against established inhibitors via molecular docking, machine learning, and MD simulations. METHODOLOGY: 202 ACE2 inhibitors (PDB ID and 6LZG), comprising repurposed antiviral compounds and specific ACE2 inhibitors, were selected for molecular docking. The two most effective compounds obtained from docking were further analyzed using machine learning to identify potential compounds with enhanced ACE2-binding affinity. To refine the dataset, molecular decoys were generated through the Database of Useful Decoys: Enhanced (DUD-E) server, and Singular Value Decomposition (SVD) was applied for data preprocessing. The Tree-based Pipeline Optimization Tool (TPOT) was then utilized to optimize the machine learning pipeline. The most promising ML-predicted compounds were re-evaluated through docking and subjected to Molecular Dynamics (MD) simulations to evaluate their structural stability and interactions with ACE2. Finally, these compounds were evaluated against the top two pre-established inhibitors using various computational tools. RESULTS: The two best pre-established inhibitors were identified as Birinapant and Elbasvir, while the best machine-learning-predicted compounds were PubChem ID: 23658468 and PubChem ID: 117637105. Pharmacophore studies were conducted on the most effective machine-learning-predicted compounds, followed by a comparative ADME/T analysis between the best ML-screened and pre-established inhibitors. The results indicated that the top ML compound (PubChem ID: 23658468) demonstrated favorable BBB permeability and a high HIA index, highlighting its potential for therapeutic applications. The ML-screened ligand demonstrated structural stability with an RMSD (0.24 nm) and greater global stability (Rg: 2.08 nm) than Birinapant. Hydrogen bonding interactions further validated their strong binding affinity. MM/PBSA analysis confirmed the ML-screened compound's stronger binding affinity, with a binding free energy of - 132.90 kcal/mol, indicating enhanced stability in complex formation. CONCLUSION: The results emphasize the efficacy of integrating molecular docking, machine learning, and molecular dynamics simulations in facilitating the rapid identification of novel inhibitors. PubChem ID: 23658468 demonstrates robust binding affinity to ACE2 and favorable pharmacokinetic properties, establishing it as a promising candidate for further investigation.
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