背景:Furoxan和苯并呋喃是含有N-氧化物官能团的化合物,以其不同的药理特性而闻名,包括抗菌和抗炎作用。本研究旨在使用N-氧化物化合物的内部文库来研究这些活性。
方法:对20种化合物进行了革兰氏阳性和革兰氏阴性菌试验,包括痤疮切杆菌(C.痤疮),与寻常痤疮的发展有关的微生物。一种化合物,(E)-4-((2-(3-羟基苯甲酰基)腙)甲基)苯氧基)-3-(苯基磺酰基)-1,2,5-恶二唑-2-N-氧化物(化合物15),表现出对痤疮梭菌的选择性抗菌活性,最小抑制浓度(MIC)值为2μg/mL。一氧化氮(NO)释放的间接测量表明,化合物15和硝酸异山梨酯,用L-半胱氨酸处理时,产生的亚硝酸盐含量为20.1%和9.95%,分别。在痤疮梭菌培养物中使用NO清除剂(PTIO)与化合物15组合导致抗微生物活性降低。表明NO释放是其作用机制的一部分。使用鼠巨噬细胞的细胞毒性评估显示,在高达0.78μg/mL的浓度下,细胞活力高于70%。
结果:白细胞介素-1β(IL1-β)和肿瘤坏死因子-α(TNF-α)的测量表明化合物15不降低这些促炎细胞因子的水平。已发现巨噬细胞或嗜中性粒细胞中诱导型一氧化氮合酶(iNOS)的持续NO产生参与寻常痤疮的炎症过程,并导致周围组织的毒性。发现在0.78μg/mL的化合物15的浓度下,鼠巨噬细胞的上清液中的亚硝酸盐水平降低,表明抗炎作用。使用皮下接种痤疮梭菌的Balb/c裸鼠进行体内研究。将化合物15的乳膏和凝胶制剂用于治疗动物,以及市售的抗痤疮药物,14天。与其他组相比,用含有5%化合物15的乳膏基质处理的动物表现出较少的棘皮病和轻度炎症浸润。突出其抗炎特性。
结论:在过氧化苯甲酰基团中观察到类似的结果,证明化合物15具有与FDA批准的药物相当的抗炎活性。这些有希望的结果表明,化合物15具有双重作用机制,具有针对痤疮梭菌的选择性抗菌活性和显着的抗炎特性,使其成为开发寻常痤疮新疗法的潜在原型。
BACKGROUND: Furoxan and benzofuroxan are compounds containing an N-oxide function, known for their diverse pharmacological properties, including antimicrobial and antiinflammatory effects. This study aimed to investigate these activities using an in-house library of N-oxide compounds.
METHODS: Twenty compounds were tested against both Gram-positive and Gram-negative bacteria, including Cutibacterium acnes (C. acnes), a microorganism implicated in the development of acne vulgaris. One compound, (E)-4-(3-((2-(3-hydroxybenzoyl)hydrazone)methyl)phenoxy)-3- (phenylsulfonyl)-1,2,5-oxadiazol-2-N-oxide (compound 15), exhibited selective antimicrobial activity against C. acnes, with a Minimum Inhibitory Concentration (MIC) value of 2 μg/mL. Indirect measurement of Nitric Oxide (NO) release showed that compound 15 and isosorbide dinitrate, when treated with L-cysteine, produced nitrite levels of 20.1% and 9.95%, respectively. Using a NO scavenger (PTIO) in combination with compound 15 in a culture of C. acnes resulted in reduced antimicrobial activity, indicating that NO release is part of its mechanism of action. Cytotoxicity assessments using murine macrophages showed cellular viability above 70% at concentrations up to 0.78 μg/mL.
RESULTS: Measurements of Interleukin-1 beta (IL1-β) and Tumor Necrosis Factor-alpha (TNF-α) indicated that compound 15 did not reduce the levels of these pro-inflammatory cytokines. Sustained NO production by inducible Nitric Oxide Synthase (iNOS) in macrophages or neutrophils has been found to be involved in the inflammatory process in acne vulgaris and lead to toxicity in surrounding tissues. Nitrite levels in the supernatant of murine macrophages were found to be decreased at a concentration of 0.78 μg/mL of compound 15, indicating an anti-inflammatory effect. In vivo studies were conducted using Balb/c nude mice inoculated subcutaneously with C. acnes. Cream and gel formulations of compound 15 were applied to treat the animals, along with commercially available anti-acne drugs, for 14 days. Animals treated with a cream base containing 5% of compound 15 exhibited less acanthosis with mild inflammatory infiltration compared to other groups, highlighting its anti-inflammatory properties.
CONCLUSIONS: Similar results were observed in the benzoyl peroxide group, demonstrating that compound 15 presented comparable anti-inflammatory activity to the FDA-approved drug. These promising results suggest that compound 15 has a dual mechanism of action, with selective antimicrobial activity against C. acnes and notable anti-inflammatory properties, making it a potential prototype for developing new treatments for acne vulgaris.