RSC medicinal chemistry最新文献

Novel thiazole analogs 3a, 3b, 4, 5, 6a-g, 8a, 8b, 9a-c, 10a-d and 11 were designed and synthesized as molecular mimetics of sunitinib. In vitro antitumor activity of the obtained compounds was investigated against HepG2, HCT-116, MCF-7, HeP-2 and HeLa cancer cell lines. The obtained data showed that compounds 3b and 10c are the most potent members toward HepG2, HCT-116, MCF-7 and HeLa cells. Moreover, compounds 3a, 3b, 6g, 8a and 10c were assessed for their in vitro VEGFR-2 inhibitory activity. Results proved that compound 10c exhibited outstanding VEGFR-2 inhibition (IC₅₀ = 0.104 μM) compared to sunitinib. Compound 10c paused the G0-G1 phase of the cell cycle in HCT-116 and MCF-7 cells and the S phase in HeLa cells. Additionally, compound 10c elevated caspase-3/9 levels in HCT-116 and HeLa cells, leading to cancer cell death via apoptosis. Furthermore, compound 10c showed a significant reduction in tumor volume in Swiss albino female mice as an in vivo breast cancer model. Docking results confirmed the tight binding interactions of compound 10c with the VEGFR-2 binding site, with its binding energy surpassing that of sunitinib. In silico PK studies predicted compound 10c to have good oral bioavailability and a good drug score with low human toxicity risks.

Stimuli-responsive smart materials for biomedical applications have gained significant attention because of their potential for selectivity and sensitivity in biological systems. Even though ample stimuli-responsive materials are available, the use of traditional Ayurvedic compounds in the fabrication of pharmaceuticals is limited. Among various materials, gels are one of the essential classes because of their molecular-level tunability with little effort from the environment. In this study, we report a simple synthesis method for multifunctional glycolipids using a starting material derived from biologically significant natural molecules and carbohydrates in good yields. The synthesized glycolipids were prone to form a hydrogel by creating a 3D fibrous architecture. The mechanism of bottom-up assembly involving the molecular-level interaction was studied in detail using SEM, XRD, FTIR, and NMR spectroscopy. The stability, processability, and thixotropic behavior of the hydrogel were investigated through rheological measurements, and it was identified to be more suitable for biomedical applications. To evaluate the potential application of the self-assembled hydrogel in the field of medicine, we encapsulated a natural drug, curcumin, into a gel and studied its pH as a stimuli-responsive release profile. Interestingly, the encapsulated drug was released both in acidic and basic pH levels at a different rate, as identified using UV-vis spectroscopy. It is worth mentioning that the gelator used for fabricating smart soft materials displays significant potential in selectively compacting the biofilm formed by Streptococcus pneumoniae. We believe that the reported multifunctional hydrogel derived from bhilawanol-based glycolipid holds great promise in medicine.

Device-related infections (DRIs) from bacterial/fungal biofilms that form on surfaces are a major cause of death in first-world countries. DRIs and the increasing prevalence of antibiotic resistant strains require development of new antimicrobials for improved antimicrobial prophylaxis. New antimicrobial prophylaxis practices necessitate novel agents to combat a broad spectrum of both fungi and bacteria, to be less toxic to patients, and to be locally administrable to prevent perturbations to a patient's microbiome. A class of antimicrobials that we have previously developed to fit these criteria is ceragenins. Here we describe the design, synthesis, and characterization of a new series of ceragenins that is composed of and degrades into endogenous compounds: cholic acid, B alanine, and glycerides. From this series we identify an optimized bioresorbable ceragenin that has comparable antimicrobial activities to other ceragenins, degrades rapidly through the action of lipase and at pH 7.2, and has a similar mechanism of action to previously developed ceragenins.

Renin-angiotensin-aldosterone system (RAAS) is crucial in cardiovascular homeostasis. Any disruption in this homeostasis often leads to numerous cardiovascular diseases (CVDs) and non-cardiovascular diseases. Small molecules that show ability toward mechanically modulating RAAS components have been developed to address this problem, thus providing opportunities for innovative drug discovery and development. This review is put forth to provide a comprehensive understanding not only on the signaling mechanisms of RAAS that lead to cardiovascular events but also on the use of small molecules targeting the modulation of RAAS components. Further, the detailed descriptions of the drugs affecting the RAAS and their pharmacodynamics, kinetics, and metabolism profiles are provided. This article also covers the limitations of the present therapeutic armory, followed by their mechanistic insights. A brief discussion is offered on the analysis of the chemical space parameters of the drugs affecting RAAS compared to other cardiovascular and renal categories of medications approved by the US FDA. This review provides structural insights and emphasizes the importance of integrating the current therapeutic regimen with pharmacological tactics to accelerate the development of new therapeutics targeting the RAAS components for improved and efficacious cardiovascular outcomes. Finally, chemical spacing parameters of RAAS modulators are provided, which will help in understanding their peculiarities in modulating the RAAS signaling through structural and functional analyses. Furthermore, this review will assist medicinal chemists working in this field in developing better drug regimens with improved selectivity and efficacy.

Hypoxia is a hallmark of the glioblastoma multiforme microenvironment and represents a promising therapeutic target for cancer treatment. Herein, we report nitroaromatic-based triazene prodrugs designed for selective activation by tumoral endogenous reductases and release of the cytotoxic methyldiazonium ion via a self-immolative mechanism. While compounds bearing a 2-nitrofuran bioreductive group were more efficiently activated by nitroreductases, 4-nitrobenzyl prodrugs 1b, 1d and 1e elicited a more pronounced cytotoxic effect against LN-229 and U-87 MG glioblastoma cell lines under hypoxic conditions when compared to temozolomide (TMZ), the golden standard for glioblastoma treatment. This cytotoxic response aligns with the increased apoptosis levels in LN-229 cells and senescence induction in U-87 MG cells, promoted by prodrugs 1d and 1e, under hypoxic conditions. These results highlight the potential of these hypoxia-activated nitroaromatic-based triazene prodrugs for selective delivery of the cytotoxic methyldiazonium ion and support further optimization to provide a safer alternative for glioblastoma treatment.

Anti-infective hydrogel is an emerging and innovative material used as an antibacterial ointment or to coat medical devices. Here, we synthesized a novel derivative of N-glycidyl d-tryptophan ether using the d-isoform of tryptophan through a ring-opening polymerization reaction. The compound was characterized using gel permeation chromatography (GPC), HPLC, ¹H NMR, ¹³C NMR, MALDI-TOF-MS, and FTIR spectroscopy. The results demonstrated its antibacterial activity by inhibiting quorum sensing and subsequent biofilm formation. In vivo studies revealed the ability of the compound to promote wound healing by reducing inflammatory cytokine levels, such as tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, the compound showed antioxidant activity by scavenging the DPPH radical due to the presence of polymeric hydroxyl acidic protons near the nitrogen. Since inflammation prompted ROS-initiated DNA strand breaks, it was also confirmed that the compound could reduce DNA strand break accumulation, as demonstrated through testing against bleomycin-induced DNA strand break accumulation. Therefore, the synthesized compound, which could be used as a base material for ointments, was found to be effective for antibacterial and wound healing actions by (a) inhibiting biofilm formation by bacteria, (b) reducing the expression of inflammatory cytokines, and (c) preventing the accumulation of DNA strand breaks through free-radical scavenging activity.

Acute lung injury (ALI) is a multifactorial respiratory disease characterized by uncontrolled inflammatory response and has high morbidity and mortality. There is currently a lack of effective drugs for ALI treatment. In this study, through nitric oxide (NO) release inhibition and cytotoxicity screening from the in-house compound library, hit compound 6 was discovered. Using 2,4,5-trichloropyrimidine as raw material, 27 new molecules were rapidly synthesized as modified products of compound 6 through nucleophilic substitution reaction and Buchwald-Hartwig reaction. Further activity evaluation and structure-activity relationship study confirmed that compound 32 was a low-toxicity, highly efficient lead compound. Action mechanism studies indicated that compound 32 can significantly reduce the inflammatory response induced by lipopolysaccharide (LPS) in RAW264.7 cells, manifested by the down-regulation of the levels of cytokines, reactive oxygen species (ROS), and the protein expression of Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) and Kelch-like ECH-associated protein-1/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 (Keap1-NRF2-HO-1). An in vivo anti-inflammatory study showed that it can reduce the severity of lung injury in the ALI model, accompanied by a reduction in the levels of inflammatory factors and related protein expression levels.

Prodrugs are masked drugs that first become pharmacologically active after undergoing a structural change in vivo. They are designed to improve physicochemical/biopharmaceutical drug properties and increase site specificity. The prodrug approach is important when developing brain-targeting drugs due to the presence of the brain barriers that seriously limit the brain entry of highly polar, multifunctional drug entities. While several excellent reviews summarize the structural modifications facilitating transport across the brain barriers, a summary of mechanisms used for the activation of the prodrug in the brain is missing. Given the high need for innovative discoveries in brain drug development, we here review the most important tools being developed since 2000 for CNS prodrug activation.

Twelve 2,4-bis-substituted quinazoline-based compounds were synthesized and screened for antiproliferative and tubulin polymerization enhancing potential. In the series, compound A4V-3 substituted with an imidazole ring displayed IC₅₀ values of 4.25 μM, 2.65 μM, and 9.95 μM, and A4V-5 with a benzotriazole substitution displayed IC₅₀ values of 3.45 μM, 7.25 μM, and 8.14 μM against MCF-7, HCT-116 and SHSY-5Y cancer cells, respectively. In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, compound A4V-3 was found to arrest the cells in the G₂/M phase of the cell cycle and induce mitochondria-mediated apoptosis. In addition, compound A4V-3 displayed significant tubulin polymerization-enhancing potential. 2,4-Bis-substituted quinazoline-based compounds showed appreciable drug-like characteristics and can be developed as potent anticancer agents.

The protozoan parasites Trypanosoma brucei and Trypanosoma cruzi, which cause human African trypanosomiasis (HAT) and Chagas disease, respectively, are responsible for considerable human suffering. Reduced case numbers and improved treatment options for HAT provide hope, but the outlook for Chagas disease is less promising, and safer, more efficacious chemotherapy is sorely needed. We previously reported the discovery and optimisation of a novel class of potent and selective trypanosomacidal 2-[(2-phenylthiazolyl)ethyl]ureas active against both T. brucei brucei and T. cruzi. In the current work, replacement of the core thiazole with alternative heterocycles has revealed that a contiguous arrangement of phenyl substituent, hydrogen-bond-accepting nitrogen, and alkyl linker are required to maintain activity. Compared to the parent thiazole, increased polarity of the core heterocycle in triazoles, tetrazoles and pyrimidines, leads to a drop in potency against T. b. brucei. A 2,6-disubsituted pyridine is tolerated but in general, 5-membered heterocycles are preferred. Analogues with oxazole, pyrazole and isomeric ('reverse') pyrazole cores displayed comparable T. b. brucei potency and selectivity to the parent thiazole, and in some cases improved lipophilic ligand efficiencies and metabolic stability. These compounds possessing more polar core heterocycles were generally 2-4 times less potent against T. cruzi (compared to T. b. brucei). This study demonstrates robust structure-activity relationships across a variety of heterocyclic scaffolds, providing many options for further optimisation of this class of compounds.