Medicinal Chemistry - Volume 21, Issue 6, 2025

Oxadiazole derivatives have shown significant potential as anti-cancer agents with low μM potencies. Some examples of drugs in this class include Raltegravir, Zibotentan, Setileuton (MK-0633), Nesapidil, Furamizole, and Tidazosin. The presence of the oxadiazole nucleus in Raltegravir exemplifies its importance in drug development, showcasing how specific structural motifs like oxadiazole can be strategically incorporated into molecules to achieve desired therapeutic effects. A large number of researchers across the globe have already developed and reported many oxadiazoles as potential anti-cancer medicines.

Therefore, we tried to discuss the anti-cancer potentials of oxadiazole derivatives reported between 2019 and 2023. The design strategies, structure-activity relationship (SAR), and protein-inhibitor interactions of potential compounds on different targets have to be identified to help the medicinal chemists design new drug-likeness oxadiazole molecules for anti-cancer therapy. Similarly, the ADMET profiles of potential oxadiazoles using the in silico SwissADME tool have to be studied.

We have highlighted the recently reported most potent oxadiazole derivatives as well as their hybrid compounds. The SAR study revealed that oxadiazole-linked pyridine, indazole, thiadiazine, quinoxaline, thiazolidine, indeno-pyrazole, thiophene, piperidine, benzimidazole, triazole, and sulphonamide showcased promising anti-cancer action. The chemico-biological interactions of potential oxadiazole compounds suggest good interactions with different amino acid residues that make them possible candidates for developing novel and effective anti-cancer therapies. Similarly, the in silico ADMET report suggested favourable physicochemical, pharmacokinetic, and drug-likeness properties of potential oxadiazole compounds.

Overall, these results will prove to be a helpful and vital tool for medicinal chemists investigating and working with oxadiazoles for anti-cancer action.

The aim is to halt the progression of liver cancer (Hepatocellular carcinoma) by suppressing the VEGF-R1 receptor using Myricetin and its de novo-designed analogues.

VEGF/VEGFR autocrine signalling promotes the growth, progression, and metastasis of Hepatocellular carcinoma, making the development of molecularly targeted therapies highly feasible. Invasive and metastatic behaviours in various cancers, including hepatocellular carcinoma (HCC), are closely monitored through the use of VEGF signalling pathway inhibitors. Specifically in HCC, VEGFR-1 facilitates the invasive capabilities of cancer cells primarily by triggering the epithelial-mesenchymal transition (EMT) process. VEGFR-1 significantly influences the activity of proteolytic enzymes that are critical for the invasive behaviour of HCC cells. Notably, a novel mechanism has been discovered where VEGFR-1 activation leads to the upregulation of MMP-9, thereby enhancing the invasiveness of HCC cells. The scientists, in their study, have elaborated on the various antiangiogenic agents developed for the treatment of HCC. They have highlighted clinical trials that explore the efficacy of these treatments, which include the application of monoclonal antibodies and small-molecule kinase inhibitors designed to target specific pathways involved in tumour angiogenesis and growth.

Creating a pharmaceutical chemistry table regarding “Structure-Activity Relationship of New Compounds on anticancer”. To do so, Myricetin and its de novo designed structured variants were used in molecular docking, molecular dynamics, cluster analyses, and ¹H NMR estimation to specifically understand and enhance the mechanism of suppressing the VEGF-R1 receptor.

Proper ligands (Myricetin and its analogues) and receptor (VEGF-R1) preparations, and optimizations were done using the density functional theory (DFT)/B3LYP function along with the 6-31G(d,p) basis set principle in the latest software programs such as Gaussian 09, Gauss View 6.0 and Avogadro. Then using PyRx and Autodock Vina 1.1.2., many molecular docking trials were achieved with 100 posed simulations in each run. An extensive cluster analysis was performed to identify the most optimal docking poses with the highest accumulation and most favourable binding interactions, ensuring the accuracy of the study. The docking configurations that exhibited the most precise and accurate poses with lowest inhibition constants were chosen as initial structured data for subsequent Molecular Dynamics (MD) simulations for each drug candidate. To verify the molecular docking results, MD runs were achieved in our supercomputers and the trajectory analyses were made. The data confirmed what was found in molecular docking results, verifying the high efficiency of the druggable molecules’ inhibition towards VEGF-R1.

Amine-derivatized Myricetin has a significantly high docking score (-10.56 kcal/mol) and great inhibition constant compared to pristine Myricetin (-4.77 kcal/mol) itself while Fluorine-derivatized Myricetin (-6.45 kcal/mol) has an affinity towards VEGF-R1 between the first two molecules. Thus, the structure-activity relationship concerning pharmaceutical chemistry aspects of all the molecules studied, yielded us a great insight into what Myricetin’s organic structure possesses towards inhibiting the progression of Liver Cancer. Also, ADME studies showed that both Amine and Fluorined-derivatized Myricetin molecules are good drug candidates.

This study highlighted the significant potential of Myricetin as an anti-cancer drug when modified with specific functional groups. Through comprehensive in silico computational analyses, our research group enhanced Myricetin's inhibitory capabilities by derivatizing its Hydroxyl group with Amine and Fluorine, resulting in improved docking scores and inhibition constants. The findings from molecular docking and MD simulations provide a promising foundation for future in vitro and in vivo investigations of these molecules as potential drugs in cancer research.

Over the past ten years, a remarkable number of changes have occurred in the field of cancer drug research. Most anticancer drugs from the first generation work by breaking down DNA, preventing its production, interfering with cell division processes, or attaching to microtubules. The potential use of tryptanthrin as well as its analogues is well documented for anticancer properties.

To design a novel hybrid of tryptanthrin analogs with expected anticancer activity.

By changing the C-6 carbonyl position of the tryptanthrin molecule, a set of 72 derivatives of substituted-6-benzylidine-6H-indolo[2,1-b] quinazoline-12-one was developed. These ligands were screened in silico using Schrodinger Glide extra precision docking against DNA topoisomerase using doxorubicin and teniposide as references to identify their potential anticancer properties. Further, these ligands were subjected to an in silico ADMET study to identify their drug likeliness.

Combined results of molecular docking and in silico ADMET study suggest that out of the total 72 ligands, 6 ligands RC 51, RC 29, RC 42, RC 3, RC 54, and RC 63 were showing very better binding affinity than the natural ligand adenylyl-imidodiphosphate and the two standard reference drugs- doxorubicin and teniposide.

Our computational approach was successful in identifying ligands that are potentially potent topoisomerase inhibitors. These can be tested further using in vitro and in vivo analysis.

Glioblastoma Multiforme (GBM), a highly aggressive and prevalent brain cancer with a higher incidence in males, has limited treatment success due to drug resistance, inadequate targeting and penetration of cancer cells, and an incomplete understanding of its molecular pathways. GBM is a highly aggressive brain cancer with limited treatment options. This study investigates the anticancer potential of synthesized pyrazole compounds against GBM cells.

A series of pyrazole derivatives were synthesized and tested for their efficacy against GBM using MTT assays. Molecular docking studies were conducted to explore the binding interactions of these compounds with GBM receptors.

Compounds 3 and 5 demonstrated significant anticancer activity, reducing cell viability more effectively than the control group. MTT assay results confirmed their potency. Molecular docking studies revealed strong binding interactions with GBM receptors, highlighting their potential as anticancer agents.

The study evaluated the anticancer activity of synthesized compounds on human GBM cells, with compounds 3 and 5 showing the most promising results. Pyrazole 3 significantly reduced cell viability at high concentrations, while both pyrazoles 3 and 5 required higher doses to achieve substantial effects, as indicated by their IC50 values. Molecular docking studies confirmed strong binding interactions with the GBM receptor, and the pharmacokinetic properties suggest their potential as anticancer agents. These results highlight compounds 3 and 5 as candidates for further investigation.

This work presents the synthesis of Ru(II)NHC complexes bearing a series of 4-fluorobenzyl group. These complexes have been characterized by a variety of spectroscopic methods (¹H NMR, ¹³C NMR, and FTIR) and by elemental analysis techniques.

These complexes' antitumor activities against SH-SY5Y (human neuroblastoma) and HCT116 (human colon cancer) were investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assay.

The results showed that all the synthesized complexes exhibited significant cytotoxic effect with low IC50 values 15 ± 0.57, 15.26 ± 0.71, 7.64 ± 0.30, 27.66 ± 0.36 and 14.45 ± 0.84 (µg/mL) respectively.

Furthermore, apoptosis assessed by double labeling with Annexin V-FITC/PI indicated that complexes 1b and 1d can effectively induce apoptosis and inhibit cell proliferation at the S phase in SH-SY5Y cells. Taken together, Ru(II)NHC complexes containing the 4-fluorobenzyl group have significant potential for the development of novel, highly effective anticancer agents.

Liver cancer is considered one of the most common types of cancer and a major cause of ephemerality worldwide having a higher prevalence rate in Asia and sub-Saharan Africa. The alpha-fetoprotein (AFP) is a serum glycoprotein that belongs to a class of onco-developmental proteins and is also involved in tumor formation.

In the current effort, a hybrid approach of virtual screening followed by pharmacophore generation and molecular dynamic simulation analyses were performed. The screened top-ranked 10 docked compounds from the selected anti-cancer compound library were utilized to generate the ligand-based pharmacophore. Virtual screening was performed two-dimensional similarity search against the selected natural compound library based on their physicochemical properties. It was observed that all the compounds from the anti-cancer compound library and natural compound library showed similar binding resides.

Therefore, the top-ranked screened compounds that showed the least binding energy and highest binding affinity against AFP, obtained through the anti-cancer drug library and natural compound library were reported. The molecular docking analyses revealed that Leu-219, His-222, Lys-242, Lys-246, His-316, Glu-318, Ala-366, Val-367, Gly-475, Ile-479, Ala-471, Asp-478 were observed as potential residues for interaction.

The observed results of virtual screening, molecular docking, and MD simulation analyses entail noteworthy observations illustrating that NC002 was a potent inhibitor. The proposed compound NC002 may have potential against liver cancer by targeting AFP based on MD simulation analyses, PCA, and MM-GBSA.

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.

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.

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-1H-pyrazol-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 (MM-GBSA) ranged from -6 to -35 kcal/mol, indicating strong SYK affinity.

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.

Development of theranostics agents targeted towards particular receptors can effectively help in the management of cancer. The overexpression of the sigma-2 receptor (S2R) in tumors establishes it as a prominent biomarker for cancer cells.

Radiotheranostics rely on the design of specific molecules having versatility in applications of diagnosis and therapy by merely changing the radioisotope. We have designed a novel radiotheranostic S2R-targeted ligand using cyclohexylpiperazine and performed docking studies to narrow down the potential efficacious ligand. The potential molecule with G-score = -7.0 kcal/mol, was then synthesized using a three steps reaction including conjugation of 2-(4-cyclohexylpiperazine-1-yl)ethyl(CYX) with DTPA chelator. Subsequently, the molecule has been radiolabelled with ^99mTc using stannous chloride as a reducing agent, and a radiolabellieng efficiency of 95.0 ± 0.59% for ^99mTc-CYX-DTPA. As proof of concept, the molecule has been evaluated for its binding affinity and specificity using sigma receptors isolated from the liver membrane homogenates of mice. The binding affinity was found to be Kd = 12.84 ± 0.395 nM; Bmax = 0.5258 ± 0.001 fmol/mg, indicating a high affinity for the receptors.

In addition, the molecule was also assessed for biocompatibility using haemolysis analysis and cytotoxicity on HEK cells and MDA-MB-23, wherein the molecule showed no significant cytotoxicity up to 72 h on HEK cells and 32.42% cytotoxicity on MDA-MB-231 cells.

The future work will concentrate on the demonstration of in vivo targeting and site-specific accumulation of the molecule along with its suitability for theranostics applications.