Introduction: The objective of exploiting benzimidazole, a chemical compound with the molecular formula C7H6N2, varies depending on its application. In this review, articles published between 2001 and 2025 were analyzed. Its adaptability and multiple chemical properties make it valuable in fields such as pharmaceuticals, materials science, and chemical research. The structural characteristics of benzimidazole allow for a wide range of modifications and applications.
Methods: The benzimidazole derivatives were synthesized and analyzed. An extensive literature search was conducted using databases such as Google Scholar, PubMed, ScienceDirect, SpringerLink, Wiley Online Library, RSC Publishing, and Eureka Select. Key synthetic methods, including Philip's reaction, oxidative/reductive cyclization, multicomponent reactions, and microwave-assisted synthesis, were illustrated using ChemDraw Ultra.
Results: This review outlines synthetic strategies for developing potent benzimidazole-based anticancer agents, highlighting their therapeutic potential through a summary of in vitro efficacy in inducing apoptosis and cell cycle arrest across various cancer cell lines.
Discussion: Benzimidazole derivatives exhibit strong in vitro anticancer activity through apoptosis and cell cycle arrest, yet face challenges such as low bioavailability and limited clinical translation. The review highlights gaps in resistance mechanisms and delivery strategies, urging the use of in vivo studies, SAR-based optimization, and clinical advancement to realize their therapeutic potential.
Conclusion: The study highlights the chemical versatility of benzimidazole scaffolds and their structure-activity relationships in the design of anticancer drugs. Key findings emphasize efficient synthetic methodologies and functional modifications that enhance bioactivity. These insights contribute to the rational development of novel, potent anticancer agents, reinforcing the value of benzimidazoles in medicinal chemistry.
Introduction: Cyclooxygenase-2 (COX-2) is a key enzyme in the inflammatory cascade and is implicated in chronic conditions, including arthritis, cancer, and cardiovascular diseases. Selective inhibition of COX-2, while sparing COX-1, is crucial to minimize gastrointestinal and renal side effects associated with non-selective NSAIDs. Computational drug discovery offers a strategic advantage for efficiently identifying novel, selective COX-2 inhibitors.
Methods: Comprehensive in-silico studies were performed, which included ligand and structurebased screening, ML-based QSAR model, ADME/toxicity profiling, and molecular dynamics simulation. Five potent COX-2 inhibitors were used as query compounds to identify a dataset of 9213 similar molecules using the SwissSimilarity Server, which employed fingerprint-based screening of the ZINC database. Subsequently, these molecules were docked into the active sites of the COX-1 and COX-2 targets using AutoDock Vina to discover selective COX-2 inhibitors.
Results: A pool of 236 compounds was selected based on docking scores (≤ -8.0 kcal/mol for COX-2 and ≥ -6.0 kcal/mol for COX-1), indicating potential selectivity. ADME/toxicity filtering narrowed the pool to 23 candidates. QSAR predictions identified 13 biologically active molecules, which were further evaluated for toxicity. Molecular dynamics simulations confirmed ten compounds with stable binding and favorable interaction profiles.
Discussion: The integrated computational workflow enabled the identification of ten highly selective COX-2 inhibitors with promising pharmacokinetic and safety profiles. These candidates demonstrated strong potential for experimental validation and development into anti-inflammatory therapeutics.
Conclusion: The in-silico studies offer valuable insights into discovering selective COX-2 inhibitors for potential therapeutic and pharmacological applications. The findings provide a strong foundation for future experimental validation and the development of anti-inflammatory medicine.
Introduction: In the discovery of anticancer drugs, Purine analogues demonstrated crucial attention due to their structural similarity to natural purines, which are essential for DNA and RNA synthesis. Cytotoxic effects are exerted by these compounds by interfering with nucleic acid metabolism, enzymatic activity and signal transduction, which is necessary for cancer cell proliferation.
Methods: This study was carried out to investigate the potential anticancer effects of purine-based hybrid compounds by evaluating their impact on cell cycle regulation, proinflammatory cytokine inhibition, and induction of apoptotic gene expression in cancer cells. The studies involve peerreviewed articles on purine analogues used in cancer therapy, which focus on molecular targets, preclinical or clinical efficacy data and structure-activity relationships (SAR).
Results: Classic purine analogues such as 6-mercaptopurine, thioguanine, and cladribine have proven effective against hematologic cancers. Recent innovations have broadened their use to solid tumours by targeting kinases (e.g., CDKs, PI3K), epigenetic regulators (e.g., DNMTs), and immune checkpoints. Improved molecular modelling and SAR studies have enhanced drug specificity and pharmacokinetics. Additionally, combining purine analogues with other chemotherapeutics or targeted agents has shown synergistic effects and potential for overcoming resistance.
Discussion: The current outlook of the purine-based anticancer agents is aimed at this review by concentrating on their mechanisms of action, the development of target-specific strategies and therapeutic targets for the enhancement of anticancer efficacy and decreasing target toxicity.
Conclusion: For the anti-cancer drugs, Purine-based compounds remain a versatile and evolving class. Their targeted design offers promising avenues for personalized cancer therapy, warranting further clinical exploration.
Introduction: Dengue infection, caused by four serotypes of the dengue virus (DENV), poses a significant global health threat, with millions of cases reported annually. RNAdependent RNA polymerase (RdRp) is an essential viral enzyme involved in the replication cycle and is a promising target for antiviral drug development. In the present study, computational methods were employed to identify novel compounds with potential inhibitory activity against DENV serotype 3 RdRp.
Methods: Molecular docking-based virtual screening approaches were used to screen a diverse library of small molecules against the three-dimensional structure of DENV-3 RdRp. Furthermore, pharmacokinetic and toxicity predictions were utilized to prioritize compounds with favorable drug-like properties. Subsequently, molecular dynamics simulation studies were performed to assess the stability and binding affinity of the predicted inhibitors.
Results: The computational studies yielded three promising DENV serotype 3 RNA-dependent RNA polymerase inhibitors, with docking scores ranging from -8.89 to -8.19 kcal/mol. MD simulations over 100 ns demonstrated stable protein-ligand complexes, with backbone RMSDs varying from 0.77 to 1.87 Å.
Discussions: Comprehensive interaction analysis revealed that Z248 and Z982 engaged key catalytic residues Arg729 and Arg737 within the palm domain, while Z389 exhibited hydrophobic stabilization through interaction with Trp795. These residues are critical for enzymatic activity, and their engagement highlights the mechanistic relevance of the identified compounds. The dynamic stability of the RdRp-ligand complexes was further validated through 100 ns molecular dynamics simulations, with both protein backbone and ligand RMSDs remaining within acceptable limits.
Conclusions: The identified inhibitors, obtained from exhaustive computational studies, represent promising candidates for further experimental validation and optimization as potential antiviral agents for the treatment of DENV-3 infections.
Introduction: The rising prevalence of cancers with chronic inflammation is a leading global health concern. Modern anticancer treatments require dual inhibitors of cyclooxygenase- 2 (COX-2) and Epidermal Growth Factor Receptor (EGFR) with minimal adverse effects.
Methods: The emergence of diaryl ether derivatives has encouraged the development of new therapeutic strategies for inflammation-linked conditions. A series of nine diaryl ether derivatives was designed, and in silico studies were performed to predict their interactions with COX- 1, COX-2, and EGFR proteins. Drug likeness and toxicity characteristics were investigated using Swiss ADME, ADMET Lab 2.0, and ProTox-3.0 tools. Furthermore, to observe the selective COX-2 inhibitory nature, a protein (bovine serum albumin (BSA)) denaturation study of the five best compounds with high binding affinities was conducted.
Results: Nine diaryl ether derivatives were synthesized and characterized using 1H-NMR, 13C NMR, LC-MS, and FT-IR spectroscopy. Based on the docking score and pharmacokinetics, compound 12a showed a significant IC50 value of 39.24 μg/mL in the BSA denaturation assay. To screen the kinetic behavior of five selected compounds with high binding affinities (11a, 12a, 12b, 12c, and 13a) with COX-2, Molecular Dynamics (MD) simulations were performed for 100 ns. MD simulations and binding free energy calculations were performed to observe the stability of the best-docked EGFR-12a complex with a docking score of -9.5 kcal/mol.
Conclusion: This study focused on the synthesis and biological analysis with theoretical explanations. Overall, diaryl ether derivatives are promising precursors for anti-inflammatory and anticancer drugs in the biomedical field.
Introduction: Histone deacetylases (HDACs) play a crucial role in gene expression, and their dysregulation is linked to various cancers. HDAC inhibitors, particularly hydroxamic acid derivatives, have shown promising anticancer effects, with several approved for clinical use. This research aimed to synthesize novel 7-hydroxycoumarin-based N-hydroxyamides, evaluate their HDAC inhibition, and assess their in vitro cytotoxic effects.
Methods: The structures of the synthesized compounds were established by analysis of their physicochemical, elemental, and spectroscopic data. HDAC, in vitro assays, and molecular docking were performed using standard procedures.
Results: The biological results showed that compounds 5d, 5e, 5j, 5l, and 7k exhibited potential cytotoxicity toward all five cancer cell lines. These compounds displayed potent cytotoxicity against the NCCIT cancer cell line with IC50 values of 4.53-1.45 μM. However, they exhibited weak to medium HDAC inhibitory activity with IC50 values ranging from 21.72 to 4.79 μM. Docking simulation studies with selected compounds revealed that compounds 5a and 7k formed stable interactions in the active site of HDAC enzyme with binding affinities ranging from -7.43 to -7.103 kcal/mol, respectively.
Discussion: The study revealed several compounds with potential HDAC inhibitory activity and cytotoxicity. However, they were still less effective in inhibiting HDACs than SAHA and Trichostatin A. Their reduced potency may be related to the length of the linker linked to the surface recognition group. This provides important insight into the future design of hydroxamic acids of this type.
Conclusion: The research results suggest that some hydroxamic acids (5a and 7k) warrant further evaluation, and these results could serve as a basis for designing more potent HDAC inhibitors and antitumor agents.
Introduction: The protozoan parasite Trypanosoma cruzi (T. cruzi) is the etiologic agent of Chagas disease, also known as American trypanosomiasis, which primarily affects the Americas and is highly prevalent in developing countries. Treatment consists of the drugs nifurtimox and benznidazole; however, both drugs have variable efficacy and cause serious adverse effects. In T. cruzi, the enzyme glyceraldehyde 3-phosphate dehydrogenase (TcGAPDH) plays an essential role in energy production and additional nuclear functions, making it a pharmacological target for the development of new trypanocidal agents. In this study, the objective was to identify new potential TcGAPDH inhibitors with trypanocidal activity.
Methods: A virtual screening based on molecular docking of FDA-approved drugs was performed, followed by in vitro biological evaluation of trypomastigotes from two T. cruzi strains.
Results: Seven FDA-approved drugs (pemetrexed, gliquidone, irbesartan, enoxacin, norfloxacin, pazopanib, and fenoprofen) had the best affinity values and a suitable interaction profile at the active site of the TcGAPDH enzyme, which had better LC50 values than the reference drugs.
Discussion: Drug repositioning using computer-aided methods reduces cost and time to find new pharmacological treatments. In this study, gliquidone (antidiabetic), irbesartan (antihypertensive), pemetrexed, and pazopanib (anticancer) are drugs with high trypanocidal activity that could be candidates for evaluation in clinical phases or used to develop new drugs to combat Chagas disease. It highlights fenoprofen, an anti-inflammatory agent, which has biological properties that help to reduce the symptomatology of the disease in the chronic stage. Additionally, it is necessary to study the mechanism of action of these compounds in detail to confirm if they have an effect on the proposed pharmacological targets.
Conclusion: Seven FDA-approved drugs are candidates for further studies leading to the development of potential new treatments for Chagas disease.
Quinolones are nitrogen-containing heterocyclic compounds that exist in natural, semisynthetic, and synthetic forms, and play a vital role as antibiotics. Their complex structure and numerous potential modifications have made them a significant focus in synthetic chemistry over the past two to three decades. The most common compound associated with quinolones is nalidixic acid, which was discovered long ago. Since then, various researchers have focused on this core as a potential pharmacophore or starting nucleus for developing new drug candidates to manage diseases, such as cancer, urinary tract infections, Alzheimer's, and tuberculosis. In this paper, we aimed to summarize the activities of quinolone hybrids discovered over the past decades. The article delivers a thorough overview of quinolones with emphasis on synthetic innovations, their mechanism of action, resistance evasion, and classification from generation to generation, along with the newer agents. Furthermore, emerging concepts, including modulation of SOS response, induction of oxidative stress, and impact of sub-inhibitory concentrations, are also explored as supplementary strategies to enhance antibacterial efficacy. Beyond their well-known antibacterial activity, quinolones also exhibit a broad range of pharmacological properties, including antimalarial, antifungal, antiinflammatory, antitubercular, anticancer, antiviral, and immunomodulatory effects. This review highlights both their diverse clinical applications and the challenges associated with their use. This article also provides a knowledgeable asset for acknowledging quinolones' chemistry, pharmacology, and future therapeutic potential.
Oxindole and its derivatives have emerged as interesting scaffolds for developing innovative anticancer medicines due to their various biological activities and capacity to target critical molecular pathways in cancer growth. The oxindole nucleus has powerful anticancer capabilities, which are exerted through various methods, including kinase inhibition, apoptosis induction, disruption of microtubule dynamics, and signaling pathway modification (PI3K/Akt, MAPK, and p53). Furthermore, oxindole-based drugs have been beneficial in combating multidrug resistance and improving the efficacy of existing chemotherapeutic treatments. The current review examines the anticancer potential of the oxindole nucleus, including structure-activity correlations, molecular targets, and methods of action. Furthermore, we discuss current advances in oxindole-derived drug design and its clinical implications, providing insights into prospective therapeutic possibilities. Understanding the molecular characteristics of oxindole derivatives can help in the rational development of new anticancer medicines with higher efficacy and selectivity.
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