Medicinal Chemistry Research最新文献

In pursuit of potent inhibitors with antiproliferative effects against breast cancer, fifteen new compounds containing a Michael Acceptor Moiety (MAM) were synthesized. The cinnamamide scaffold, a natural source of MAM, was chosen for its versatile structural framework, which offers rich potential for chemical modifications and optimization of biological activity. The first step consisted of obtaining five unprotected amines (5a-e), yielding between 40% and 90% yield. Subsequently, these amines were coupled with various cinnamic acid derivatives, resulting in target products in yields ranging from 30% to 94%. This study aimed to assess the impact of these compounds on cell viability, focusing on two human breast cancer cell lines, MCF-7 and MDA-MB-231. Among the compounds examined, eight (7a, 7b, 7d, 7f-i, 7l) showed activity against MDA cells (IC₅₀ range: 2.5–53.0 µM), and five (7b, 7 g-i, 7l) showed activity against MCF-7 cells (IC₅₀ range: 11.2–50.6 µM). 7f was the most active molecule, with an IC₅₀ of 2.5 µM toward MDA cells and a good selective index (SI = 7.9) toward a normal cell line (MCF-10A). In silico ADME studies were carried out with prospective compounds using the SwissADME tool.

Iridoid glycosides are a class of chemical structures with various pharmacological activities and have excellent research potential. However, the poor stability, water solubility, and oral bioavailability limit their practical application and clinical research. In this review, we systematically summarize the structural modifications of iridoid glycosides and attempt to demonstrate the structure-activity relationship between chemical modifications on iridoid skeleton and glycosidic bond, noting that some derivatives exhibit satisfactory pharmacological activities. This review aims to provide valuable assistance for further research and clinical application of derivatives, to provide ideas for the design and synthesis of novel iridoid glycosides, and to provide a research basis for developing new drugs with higher activity in the future.

The recent FDA-approval of lenacapavir (LEN, GS-6207) and the subsequent discovery of GSK878 strongly validate HIV-1 capsid protein (CA) as a target for antiviral development. However, multiple single mutations drastically reduced the susceptibility of HIV-1 to both GS-6207 and GSK878, necessitating the design and synthesis of novel sub-chemotypes. With the aid of induced-fit molecular docking, we have designed a few new hybrids combining the quinazolinone scaffold of GSK878 and an N-terminal cap from other CA-targeting chemotypes. We have also worked out a modular synthesis of these novel subtypes. Although these new analogs only weakly inhibited HIV-1 and produced relatively small shifts in the thermal shift assay against pre-assembled CA hexamers, the design and synthesis reported herein inform future design and synthesis of structurally more elaborate analogs for improved potency.

Herein, the privilege in favor of biological importance of indole-containing scaffolds related to the semi-synthetic and extracted from natural sources is summarized. Such compounds have shown notable medicinal significance and are used in the treatment of various carcinomas after FDA approval. The chemistry of indoles’ skeleton derivatives showed various conformations at specific conditions, including tautomerization, when they came into contact with polar solvents; consequently, such phenomena are responsible for enhancing the biological effect on enzymes. In the foregoing review study in the past decade, we demonstrated the biological significance and the transformation of drug analysis owing to resonating structures. Functionalize groups, it was noted that pi-bonds-unsaturated functions, sp^1/2/3 hybridized methylene groups, cyclic ethers, primary amino groups, halogens, and staggered conformations displayed the most potent active drug-like molecules. The aim of this report is that drugs like lead molecules could be derivatized for the discovery of more effective drugs on the basis of their possible active sites on the surface in the future.

The genus Plumeria of the Apocynaceae family has a rich history of traditional medicines supported by empirical evidences. This review consolidates diverse biological attributes, phytochemical compositions, physical properties (melting point, shape, optical rotation, etc.), and analytical data (UV, IR, Mass spectroscopic data, elemental analysis) of various species of Plumeria. The review covered the chemistry of wide range of natural compounds like iridoids, triterpenoids, alkaloids, flavonoids, steroids, cardiac glycosides, quinones, anthocyanins, cardenolides, fatty acid esters, lignans, coumarins, etc. found in various species of the genus Plumeria. Analytical techniques including chromatography, IR, UV, and mass spectroscopy have significantly contributed to elucidating the complex chemical profiles of extracts of various species of Plumeria which are systematically presented in a tabular format. The review also defines the historical background, geographical distribution, and traditional uses of various species of the genus Plumeria. The review also includes the mechanisms of action and biotransformation of compounds, providing a deeper understanding of their therapeutic potential. The comprehensive review reveals the significance of the natural products isolated from a number of species of genus Plumeria. It is also suggestive that there is an extensive scope for further investigation to explore new therapeutic components of the genus Plumeria.

G-quadruplex DNA secondary structures are formed in guanine-rich sequences and have been found to play an important role in regulating different biological processes. Indeed, guanine-rich sequences with the potential to form G-quadruplexes are present in different regions in the human genome, such as telomeres and the promoter region of different genes, including oncogene promoters. Thus, the rational design of small molecules capable of interacting, stabilising or damaging with high specificity these secondary structures represents an important strategy for the development of potent anticancer drugs. In this review, we highlight the interaction between G-quadruplex structures and their ligands, specifically emphasising the role of metal complexes. We provide detailed structural insight into the binding modes of metal complex-G-quadruplex interaction by analysing 18 sets of coordinates from X-ray and NMR currently available in the Protein Data Bank (PDB), with a primary focus on X-ray structural data.