Medicinal Chemistry - Volume 21, Issue 4, 2025

Monkeypox, a viral zoonotic disease akin to smallpox, has posed significant public health challenges, particularly in Africa. Recent outbreaks, including those in India, underscore the global threat it poses.

In this study, we explore a novel approach to combat monkeypox virus (MPXV) infection by targeting its surface proteins, crucial for viral entry and fusion.

Employing advanced computational techniques, we predict and refine the 3D structures of MPXV surface proteins and human antimicrobial peptides (hAMPs), specifically Histatin 1, 3, and their cleaved product, Histatin 5 (HIS 5). Further, molecular docking was carried out for MPXV surface proteins with hAMP HIS using HDOCK and Cluspro 2.0. Protein-peptide interactions were analyzed using PdbSum. Finally, the physicochemical properties of HIS peptides were determined using CamSol.

Our findings suggest HIS 5 as a potential therapeutic peptide against MPXV, warranting further investigation through in vitro and in vivo studies.

This study sheds light on the efficacy of the HIS family in targeting MPXV and advocates for continued exploration of HIS 5's antiviral effects.

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.

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.

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.

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.

Ethacrynic acid is a dynamic agent holding alpha-beta unsaturated carbonyl unit in its structure which imparts superiority and extraordinary advantage of displaying multiple biological activities such as anticancer, antiviral, anti-malarial effect, diuretic effect and inhibits the Glutathione-s-transferase p1-1 enzyme which produces hindrance in the pathway of apoptosis. Ethacrynic acid is an inhibitor of Glutathione-s-transferases. EtA by itself act as an anti-cancer agent at higher concentration and also increases effectiveness of other compounds used in cancer treatment by preventing their detoxification, all these facts attracted our attention to develop and evaluate novel structural analogues of ethacrynic acid for their inhibitory effect on GSTs and anti-cancer activity in breast cancer.

By attending rational drug design perspectives the research is aimed to develop and evaluate novel structural analogues of ethacrynic acid as Inhibitors of GSTs enzyme and with anti-breast cancer activity.

Designed compounds were synthesized as per convenient route shown in the scheme of synthesis. Molecular docking studies were done against GSTP1-1 (PDB:3HJO). Structures of novel synthesized molecules were confirmed by spectral characterization such as FTIR, ¹HNMR, ¹³CNMR and Mass spectrometry. ADME studies were done to ensure safety and drug like properties of the compounds. Ten structural analogues of ethacrynic acid were synthesized and evaluated for their inhibitory effect on activity of Glutathione-s-transferases which was measured by performing assay method. In-vitro anti-breast cancer activity was done on MCF-7 and MDAMB-231 cell line by MTT assay.

Compound A3, A5 and A6 were found with greater inhibition of the activity of GSTs and maximum anti-proliferative activity in breast cancer.

We have effectively developed novel compounds possessing structural resemblance with ethacrynic acid Compounds of the series has shown moderate to higher inhibitory effect on GSTs and anti-proliferative activity in breast cancer. The compound A3 was found to be promising agent with high level of potency in each biological response. The research studies presented here may be an enlightening path in development of novel therapeutic agents with high level of inhibition in the activity of GSTs and anti-breast cancer effect.