RSC medicinal chemistry最新文献

PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that are in clinical development through the prism of their physicochemical properties. In particular, the optimisation of the various components of PROTACs together with the difficulties faced by medicinal chemists seeking to achieve oral bioavailability in this challenging space are outlined. Guidance, opinion and advice based on the authors' own experiences in this area are offered in the hope this may be useful to others working in this fascinating frontier of drug discovery.

Irreversible targeted covalent inhibitors, in the past regarded as inappropriately reactive and toxic, have seen a recent resurgence in clinical interest. This paradigm shift is attributed to the exploitation of the two-step mechanism, in which a high affinity and selectivity (i.e., low K _I) scaffold binds the target and only then does a pendant low intrinsic reactivity warhead react with the target (moderate k _inact). This highlights the importance of evaluating inhibitors by deriving both their K _I and k _inact values. The development of methods to evaluate these inhibitors by accounting for their time-dependent nature has been crucial to the discovery of promising clinical candidates. Herein, we report all the practical kinetic methods available to date to derive k _inact and K _I values. These methods include direct observation of covalent modification, continuous assay (Kitz & Wilson) evaluation, and discontinuous incubation and pre-incubation time-dependent IC₅₀ assays. We also provide practical guidelines and examples for performing these assays, comparison of their utility, and perspectives for their extended applications. This review aims to provide clarity about the use of these methods for reporting complete inhibitor kinetic profiles, guiding irreversible drug development towards increased target affinity and selectivity, while modulating in vivo stability and on-target reactivity.

In the current study, we have designed and prepared a series of quinoxaline-based compounds, which were derived from o-phenylenediamine. Among them, compounds 5m-5p displayed good to moderate antibacterial activity with MICs of 4-16 μg mL^-1 against S. aureus, 8-32 μg mL^-1 against B. subtilis, 8-32 μg mL^-1 against MRSA and 4-32 μg mL^-1 against E. coli, respectively. Compound 5p, identified as a potent broad-spectrum antibacterial agent, demonstrated the strongest inhibitory effects against a range of bacterial strains and low cytotoxicity, thereby warranting further investigation. Compound 5p not only demonstrated the ability to disperse established bacterial biofilms but also induced a slower development of bacterial resistance compared to norfloxacin. Moreover, bactericidal time-kill kinetic studies revealed that at a high concentration of 3MIC, compound 5p was capable of directly killing MRSA cells. The subsequent postcontact effect (PCE) results showed that the growth rate of viable bacteria (MRSA) was greatly impacted and did not recover in less than 24 hours, even after antibacterial agent 5p was removed. The drug-like properties and ADME prediction exhibited that 5m-5p obeyed Lipinski's rule of five and therefore presumably maintained moderate to good bioavailability and human intestinal absorption rate when administered orally. Mechanistic investigations have elucidated that compound 5p exerted its antibacterial effect by compromising the structural integrity of bacterial cell membranes, resulting in the leakage of intracellular constituents and ultimately causing bacterial demise. Further studies in vivo have demonstrated that 5p exhibited potent antibacterial efficacy against MRSA in murine corneal infection models, particularly at elevated concentrations. The current dataset has also been meticulously analyzed to delineate the structure-activity relationships (SARs) of the synthesized compounds.

The emergence of the mobile colistin resistance (mcr) gene is a demonstrable threat contributing to the worldwide antibiotic resistance crisis. The gene is encoded on plasmids and can easily spread between different bacterial strains. mcr encodes a phosphoethanolamine (pEtN) transferase, which catalyses the transfer of the pEtN moiety from phosphatidylethanolamine to lipid A, the head group of lipopolysaccharides (LPS). This neutralises the overall negative charge of the LPS and prevents the binding of polymyxins to bacterial membranes. We believe that the development of polymyxin adjuvants could be a promising approach to prolong the use of this important class of last-resort antibiotics. This review discusses recent progress in the identification, design and development of adjuvants to restore polymyxin sensitivity in these resistant bacteria, and focuses on both MCR inhibitors as well as alternative approaches that modulate polymyxin resistance.

Invasive fungal infections caused by C. albicans are becoming increasingly serious and there is an urgent need for exploring new antifungal drugs. In the present work, a series of new azole derivatives containing a 1,2,3-triazole moiety have been prepared, and in vitro antifungal activity have been evaluated. The results revealed that most compounds showed excellent antifungal activity against C. albicans SC5314 and drug-resistant SC5314-FR. In particular, compounds 4h, 4j, 4l, 4s and 4w exhibited better antifungal activity than FLC. The preliminary mechanism study indicated that 4s could damage the integrity of the cell structure, increase the permeability of the cell membrane, and cause the leakage of cell contents of C. albicans. The molecular docking study indicated that 4s showed an obvious binding site with the target CYP51 (PDB ID: 5TL8). Therefore, 4s could be considered as a new antifungal agent targeting CYP51 for further study.

A series of amides of selected plant triterpenoids, moronic acid and morolic acid, with the tripeptides MAG and GAM, was designed and synthesized. Two required tripeptides 5 and 10 were synthesized by a step-wise chain elongation of the ethyl esters of either glycine or l-methionine at their N-terminus using Boc-protected amino acids in each step. The tripeptides 5 and 10 were used for the synthesis of 13-23, the derivatives of moronic acid (11) and morolic acid (12), to get a series of amide derivatives of the less frequently studied triterpenoids 11 and 12. The target compounds, and their intermediates, were subjected to an investigation of their antimicrobial, antiviral and cytotoxic activity. Selectivity of the pharmacological effects was found. Generally, the target compounds inhibited only the G⁺ microorganisms. Compound 16 inhibited Staphylococcus aureus (I = 99.6%; c = 62.5 μM) and Enterococcus faecalis (I = 85%; c = 250 μM). Several compounds showed moderate antiviral effects, both anti-HIV-1, 19 (EC₅₀ = 57.0 ± 4.1 μM, CC₅₀ > 100 μM), 20 (EC₅₀ = 17.8 ± 2.1 μM, CC₅₀ = 41.0 ± 5.2 μM) and 23 (EC₅₀ = 12.6 ± 0.82 μM, CC₅₀ = 38.0 ± 4.2 μM), and anti-HSV-1, 22 (EC₅₀ = 27.7 ± 3.5 μM, CC₅₀ > 100 μM) and 23 (EC₅₀ = 30.9 ± 3.3 μM, CC₅₀ > 100 μM). The target compounds showed no cytotoxicity in cancer cells, however, several of their intermediates were cytotoxic. Compound 21 showed cytotoxicity in HeLa (IC₅₀ = 7.9 ± 2.1 μM), G-361 (IC₅₀ = 8.0 ± 0.6 μM) and MCF7 (IC₅₀ = 8.6 ± 0.2 μM) cancer cell lines, while being non-toxic in normal fibroblasts (BJ; IC₅₀ > 50 μM).

New meso-substituted AB₃-type phenothiazinyl porphyrins and ferrocenylvinyl phenothiazinyl porphyrin were synthesised by Suzuki-Miyaura and Mizoroki-Heck cross-coupling reactions, respectively. The free porphyrins were further used in the synthesis of new indium(iii) or zinc(ii) porphyrin complexes. All porphyrins exhibit red fluorescence emission in solution, a property that remains unimpaired following internalisation in ovarian A2780 cancer cells, as evidenced by fluorescence microscopy images. The In(iii) phenothiazinyl porphyrin complexes show a higher quantum yield of fluorescence emission (2aΦ _F = 30%, 4aΦ _F = 29%, 5aΦ _F = 28%) compared to the free base porphyrin precursors, or Zn(ii) complex 4b (Φ _F = 10%). The potential of novel phenothiazinyl porphyrins to act as photosensitisers was evaluated using two distinct approaches. The first was through the measurement of the singlet oxygen quantum yield Φ _Δ(¹O₂), while the second employed in vitro measurements of metabolic activity, oxidative stress, nuclear factor-erythroid 2 related factor 2 (Nrf-2) activation and tumour necrosis factor-alpha (TNF-α) under both dark and light irradiation conditions. As reflected by the IC₅₀ values, the most potent cytotoxicity of the phenothiazinyl porphyrins against the A2780 cells was observed for In(iii) ferrocenylvinyl phenothiazinyl porphyrin 4a (36.38 μM), the remaining compounds are less cytotoxic. The reduction in metabolic activity was observed in A2780 ovarian tumour cells treated with 4a and 6a and exposed to light compared to treatment in the absence of light. The oxidative stress, TNF-α and Nrf-2 transcription factor were particularly notable when A2780 cells were treated with 4a and subsequently photoirradiated, the oxidative stress was linked to the highest value of Φ _Δ(¹O₂) recorded for 4a (60%).

The prevalence of antibacterial resistance has become one of the major health threats of modern times, requiring the development of novel antibacterials. Antimicrobial peptides are a promising source of antibiotic candidates, mostly requiring further optimization to enhance druggability. In this study, a series of new antimicrobial peptides derived from lactomodulin, a human microbiome natural peptide, was designed, synthesized, and biologically evaluated. Within the most active region of the parent peptide, linear peptide LM6 with the sequence LSKISGGIGPLVIPV-NH₂ and its cyclic derivatives LM13a and LM13b showed strong antibacterial activity against Gram-positive bacteria, including resistant strains, and Gram-negative bacteria. The peptides were found to have a rapid onset of bactericidal activity and transmission electron microscopy clearly shows the disintegration of the cell membrane, suggesting a membrane-targeting mode of action.

In this work, we report on the synthesis and properties of a new sensitizer for photodynamic therapy applications, constituted by a ruthenium(ii) complex (1) featuring a ligand inspired from natural isoquinoline alkaloids. The spectroscopic analysis revealed that 1 is characterized by an intense red emission (λ _em = 620 nm, Φ = 0.17) when excited at 550 nm, a low energy radiation warranting for a safe therapeutic approach. The phototoxicity of 1 on human breast cancer (Hs578T) and melanoma (A375) cell lines was assessed after irradiation using a LED lamp (525 nm, total fluence 10 J cm^-2). In vitro biological assays indicated that the cytotoxicity of 1 was significantly enhanced by light reaching IC₅₀ values below the micromolar threshold. The cell damage induced by 1 proved to be strictly connected with the overproduction of reactive oxygen species (ROS) responsible for mitochondrial dysfunction leading to the activation of caspases and then to apoptosis, and for DNA photocleavage leading to cell cycle arrest.

The development of H₂S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H₂S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1-3 and I1a-e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H₂S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1-3 exhibit slow and similar H₂S release to sulforaphane, the release from compounds I1a-e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.