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Acridone derivatives, which have been shown to have in vitro and in vivo activity against Plasmodium spp, inhibit Toxoplasma gondii proliferation at picomolar concentrations. Using enzymatic assays, we show that acridones inhibit both T. gondii cytochrome bc1 and dihydroorotate dehydrogenase and identify acridones that bind preferentially to the Qi site of cytochrome bc1. We identify acridones that have efficacy in a murine model of systemic toxoplasmosis. Acridones have potent activity against T. gondii and represent a promising new class of preclinical compounds.

An aromatic alkaloid-rich 'absolute' extract from inhibited at 62.5 μg.mL and at 500 μg.mL A loss of activity upon fractionation indicated possible synergistic effects. Three new acridones, gossweicridone A ( ), B ( ) and C ( ) and known compounds from the extract were inactive. Combinations of compounds showed that a sub-fraction containing mixtures of minor compounds with ( )-caryophyllene augmented activity by 50-folds, with MIC values of 19.6 μg.mL for and 375.0 μg.mL for , demonstrating potent ΣFIC values of 0.02 and 0.375 respectively. From the active sub-fraction, three compounds were assigned as tecleanatalensine B, 13 -hydroxy-9 ,11 ,15 -octadecatrienoic acid and normelicopine. In combination with ( )-caryophyllene they separately demonstrated MIC values of 18 μg.mL , 34 μg.mL and 16 μg.mL respectively against . The synergistic combinations were more potent with addition of pheophytin A, suggesting that the synergistic antifungal effect of the extract is multi-layered.

Novel N-acylhydrazone derivatives from acridone have been synthesized by condensation of acridone acetohydrazide and various aldehyde. The novel acylhydrazones were tested for their in-vitro antibacterial activity against human pathogenic strains. The MIC results indicate that compound 3f displayed high antibacterial potential against Pseudomonas putida with MIC = 38.46 µg/mL, which is very close to that obtained with the commercial antibiotic. The synthesized compounds were subjected for docking studies to understand the interaction of our compounds and transcriptional regulator enzyme of pseudomonas putida and DNA gyrase complex of Staphyloccocus aureus.

Background Acridone alkaloids are heterocyclic compounds that exhibit a broad-range of pharmaceutical and chemotherapeutic activities, including anticancer, antiviral, anti-inflammatory, antimalarial, and antimicrobial effects. Certain plant species such as Citrus microcarpa, Ruta graveolens, and Toddaliopsis bremekampii synthesize acridone alkaloids from anthranilate and malonyl-CoA. Results We synthesized two acridones in Escherichia coli. Acridone synthase (ACS) and anthraniloyl-CoA ligase genes were transformed into E. coli, and the synthesis of acridone was examined. To increase the levels of endogenous anthranilate, we tested several constructs expressing proteins involved in the shikimate pathway and selected the best construct. To boost the supply of malonyl-CoA, genes coding for acetyl-coenzyme A carboxylase (ACC) from Photorhabdus luminescens were overexpressed in E. coli. For the synthesis of 1,3-dihydroxy-10-methylacridone, we utilized an N-methyltransferase gene (NMT) to supply N-methylanthranilate and a new N-methylanthraniloyl-CoA ligase. After selecting the best combination of genes, approximately 17.3 mg/L of 1,3-dihydroxy-9(10H)-acridone (DHA) and 26.0 mg/L of 1,3-dihydroxy-10-methylacridone (NMA) were synthesized. Conclusions Two bioactive acridone derivatives were synthesized by expressing type III plant polyketide synthases and other genes in E. coli, which increased the supplement of substrates. This study showed that is possible to synthesize diverse polyketides in E. coli using plant polyketide synthases.

We report the chemistry and biological activities of a Cameroonian Citrus clementina Hort. Ex Tanaka, a vegetatively propagated species. The compounds isolated from this plant were determined to be...

Three new compounds comprising two coumarins, paramicoumarins A (1) and B (2), and an acridone alkaloid, paramiacridone (3), together with seven known compounds, were isolated from the n-hexane extract of the roots of Paramignya trimera (Rutaceae). Their structures were elucidated using spectroscopic methods, mainly 1D and 2D NMR. α-Glucosidase inhibition and DPPH radical scavenging activity of the compounds and fifteen other compounds previously isolated from the roots of this plant were evaluated. Most of the compounds exhibited stronger α-glucosidase inhibitory activity than acarbose, the positive control (IC50 = 223.0 μM), and the new compounds paramiacridone (3) and paramicoumarin B (2) showed good inhibitory effect (IC50 = 62.5 and 65.5 μM, respectively). In the DPPH test for radical scavenging activity, the acridone alkaloid glycocitrin III (17) exhibited the highest antioxidant activity (IC50 = 84.2 μM) (compared with the positive control, ascorbic acid, IC50 = 152.7 μM).

The present article is a systematic and constructive review of the traditional medicinal uses, chemistry, pharmacology, toxicology, and formulation aspects of Glycosmis species. The genus Glycosmis comprise 51 accepted species broadly distributed in Australia, China, India, and South-East Asia. Traditionally, Glycosmis species are used in folk medicines to treat cancer, anaemia, rheumatism, fever, cough, liver-related problems, skin ailments, intestinal worm infections, wounds, and facial inflammation. This review aims to provide readers with the latest information highlighting chemical constituents isolated from the Glycosmis species, plant parts utilized for their isolation and their pharmacological activities. So far, 307 chemical constituents have been isolated and characterized from different species of the genus Glycosmis; among these constituents, alkaloids, flavonoids, terpenoids, phenolics, and sulphur-containing amides are the major bioactive compounds. Modern pharmacological studies have shown that the crude extracts and compounds isolated from this genus exhibit a broad spectrum of biological activities like anticancer, antimicrobial, anti-inflammatory, antipyretic, antidiabetic, antioxidant, larvicidal, insecticidal, hepatoprotective, wound healing, antiviral, antidiarrheal, and anxiolytic. The carbazole and acridone alkaloids from this genus have shown potential anticancer activity in various in vitro and in vivo studies. Rare scaffolds like dimeric carbazoles, dimeric acridone alkaloids, flavanocoumarins and sulphur-containing amides from this genus need further exploration for their potential bioactivity. This article also briefs about the toxicological screening and discusses various polyherbal and nano formulation aspects of Glycosmis species. Most of the pharmacological studies reported from this genus were carried out in vitro. An in-depth in vivo and toxicology evaluation of the crude extracts and isolated specialized compounds is required to explore the full therapeutic potential of this genus.

Upregulation of platelet-derived growth factor receptor β (PDGFR-β) has been found to be associated with development of various types of cancers, which has become an attractive target for anti-tumor treatment. Previously, we have synthesized and studied an acridone derivative B19, which can selectively bind to and stabilize oncogene c-myc promoter i-motif, resulting in down-regulation of c-myc transcription and translation, however its effect on tumor cells apoptosis requires improvement. In the present study, we synthesized a variety of B19 derivatives containing a known anti-cancer fluorescent chromophore naphthalimide for the purpose of enhancing anti-cancer activity. After screening, we found that acridone-naphthalimide derivative WZZ02 could selectively stabilize PDGFR-β promoter G-quadruplex and destabilize its corresponding i-motif structure, without significant interaction to other oncogenes promoter G-quadruplex and i-motif. WZZ02 down-regulated PDGFR-β gene transcription and translation in a dose-dependent manner, possibly due to above interactions. WZZ02 could significantly inhibit cancer cell proliferation, and induce cell apoptosis and cycle arrest. WZZ02 exhibited tumor growth inhibition activity in MCF-7 xenograft tumor model, which could be due to its binding interactions with PDGFR-β promoter G-quadruplex and i-motif. Our results suggested that WZZ02 as a dual G-quadruplex/i-motif binder could be effective on both oncogene replication and transcription, which could become a promising lead compound for further development with improved potency and selectivity. The wide properties for the derivatives of 1,8-naphthalimide could facilitate further in-depth mechanistic studies of WZZ02 through various fluorescent physical and chemical methods, which could help to further understand the function of PDGFR-β gene promoter G-quadruplex and i-motif.

As part of our continuing search for potent inhibitors of tubulin polymerization, two novel series of 42 10-(4-phenylpiperazine-1-carbonyl)acridin-9(10H)-ones and N-benzoylated acridones were synthesized on the basis of a retrosynthetic approach. All newly synthesized compounds were tested for antiproliferative activity and interaction with tubulin. Several analogs potently inhibited tumor cell growth. Among the compounds tested, 10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)acridin-9(10H)-one (17c) exhibited excellent growth inhibitory effects on 93 tumor cell lines, with an average GI50 value of 5.4 nM. We were able to show that the strong cytotoxic effects are caused by disruption of tubulin polymerization, as supported by the EBI (N,N'-Ethylenebis(iodoacetamide)) assay and the fact that the most potent inhibitors of cancer cell growth turned out to be the most efficacious tubulin polymerization inhibitors. Potencies were nearly comparable or superior to those of the antimitotic reference compounds. Closely related to this, the most active analogs inhibited cell cycling at the G2/M phase at concentrations down to 30 nM and induced apoptosis in K562 leukemia cells. We believe that our work not only proves the excellent suitability of the acridone scaffold for the design of potent tubulin polymerization inhibitors but also enables synthetic access to further potentially interesting N-acylated acridones.

Leishmaniasis treatment is often carried out with drugs of high toxic potential and high cost, and satisfactory therapeutic response is not usually observed. In this context, searching for therapeutic alternatives is urgent. This study seeks to evaluate the antileishmanial potential of alkaloids from plants. The search for scientific papers occurred at Pubmed, CAPES Journal Portal (PPC), Virtual Health Library (VHL) and COCHRANE using the descriptors: alkaloid and antileishmanial. The inclusion criteria were studies about alkaloids isolated from plants and tested against Leishmania parasite. A total of 805 publications were found in Pubmed, 825 in PPC, 4 in VHL and none in COCRHANE. After reading the titles and abstracts, articles containing other biological evaluations (350), chemical studies such as docking and material characterizations (388), evaluation of extracts and fractions activities (406) which did not fit in this research or were in duplicate (377) were excluded. Acridone and all the naphthylisoquinolinic and tetrahydroisoquinolinic alkaloids were active or moderately active against Leishmania promastigotes or amastigotes, and indolizidine was active against both forms. The β-carbolines were inactive or moderately active against Leishmania promastigotes, with the exception of flavopereirine. The indolizidine alkaloid was the most promising as a future drug candidate, since it was very active against both forms of Leishmania. El tratamiento de la leishmaniasis se realiza a menudo con fármacos de alto potencial tóxico y elevado coste, y no suele observarse una respuesta terapéutica satisfactoria. En este contexto, la búsqueda de alternativas terapéuticas es urgente. Este estudio busca evaluar el potencial antileishmania de los alcaloides de las plantas. La búsqueda de artículos científicos se realizó en Pubmed, CAPES Journal Portal (PPC), Virtual Health Library (VHL) y COCHRANE utilizando los descriptores: alcaloide y antileishmania. Los criterios de inclusión fueron estudios sobre alcaloides aislados de plantas y probados contra el parásito Leishmania. Se encontraron un total de 805 publicaciones en Pubmed, 825 en PPC, 4 en BVS y ninguna en COCRHANE. Después de leer los títulos y resúmenes, los artículos que contienen otras evaluaciones biológicas (350), estudios químicos como el atraque y caracterización de materiales (388), evaluación de extractos y actividades de fracciones (406) que no encajaban en esta investigación o estaban por duplicado (377) fueron excluidos. La acridona y todos los alcaloides naftilisoquinolínicos y tetrahidroisoquinolínicos fueron activos o moderadamente activos contra los promastigotes o amastigotes de Leishmania, y la indolizidina fue activa contra ambas formas. Las β-carbolinas fueron inactivas o moderadamente activas contra promastigotes de Leishmania, con la excepción de la flavopereirina. El alcaloide indolizidina fue el más prometedor como futuro fármaco candidato, ya que fue muy activo contra ambas formas de Leishmania. O tratamento da leishmaniose costuma ser realizado com fármacos potencialmente tóxicos e de alto custo, não sendo habitualmente observada resposta terapêutica satisfatória. Nesse contexto, a busca por alternativas terapêuticas é urgente. Este estudo visa avaliar o potencial antileishmania de alcaloides de plantas. A busca de artigos científicos ocorreu no Pubmed, Portal de Periódicos CAPES (PPC), Biblioteca Virtual em Saúde (VHL) e COCHRANE utilizando os descritores: alcaloide e antileishmania. Os critérios de inclusão foram estudos sobre alcaloides isolados de plantas e testados contra o parasita Leishmania. Um total de 805 publicações foi encontrado no Pubmed, 825 no PPC, 4 no VHL e nenhum no COCRHANE. Após a leitura dos títulos e resumos, artigos contendo outras avaliações biológicas (350), estudos químicos como docking e caracterizações de materiais (388), avaliação de atividades de extratos e frações (406) que não se enquadraram nesta pesquisa ou estavam em duplicata (377) foram excluídos. A acridona e todos os alcaloides naftilisoquinolínicos e tetrahidroisoquinolínicos foram ativos ou moderadamente ativos contra promastigotas ou amastigotas de Leishmania, e a indolizidina foi ativa contra ambas as formas. As β-carbolinas foram inativas ou moderadamente ativas contra promastigotas de Leishmania, com exceção da flavopereirina. O alcaloide indolizidina foi o mais promissor como futuro candidato a fármaco, pois era muito ativo contra ambas as formas de Leishmania.

Exosomal microRNAs (miRNAs) are vital biomarkers for early diagnosis and prognosis monitoring of cancer. Yet, convenient and controllable detection of exosomal miRNA still remains challenges because of lacking of adequately simple and robust assay platforms. In this paper, it is first time to study the visible-light-induced oxidase mimic activity of 10-methyl-2-amino-acridone (MAA) being able to be switched by Cu2+ and DNA. Based on this phenomenon, a series of visual molecular logic gates are constructed, and a colorimetric strategy has been developed to achieve exosomal microRNA-21 (miR-21) detection with a signal amplification approach. The visible-light-induced oxidase mimic activity of MAA can be inhibited by Cu2+. In presence of target, a large amount of capture probes partly complementary with miR-21 are hydrolyzed with the assist of duplex-strand specific nuclease (DSN), releasing guanine-rich oligodeoxynucleotides that can chelate Cu2+, resulting in catalytic activity of MAA being recovered under irradiation. This strategy allows the detection of miR-21 with a light modulating temporal controllable manner, and the linear range is from 50 fM to 3000 fM with the limit of detection (LOD) being 44.76 fM. More importantly, the proposed method can achieve quantitative measurement of exosomal miR-21 that is derived from three-dimensional multicellular tumor spheroids with different size, which is able to monitor the growth of tumor spheroids. This work is potential to provide a feasible tool for application in exosomal miRNAs-based cancer diagnosis. Ultimately, MAA is expected to be a signal probe in biomedical field by virtue of its fascinating visible-light-induced oxidase mimic activity.

Simple and robust assays to monitor enzymatic ATP cleavage with high efficiency in real‐time are scarce. To address this shortcoming, we developed fluorescently labelled adenosine tri‐, tetra‐ and pentaphosphate analogues of ATP. The novel ATP analogues bear — in contrast to earlier reports — only a single acridone‐based dye at the terminal phosphate group. The dye's fluorescence is quenched by the adenine component of the ATP analogue and is restored upon cleavage of the phosphate chain and dissociation of the dye from the adenosine moiety. Thereby the activity of ATP‐cleaving enzymes can be followed in real‐time. We demonstrate this proficiency for ubiquitin activation by the ubiquitin‐activating enzymes UBA1 and UBA6 which represents the first step in an enzymatic cascade leading to the covalent attachment of ubiquitin to substrate proteins, a process that is highly conserved from yeast to humans. We found that the efficiency to serve as cofactor for UBA1/UBA6 very much depends on the length of the phosphate chain of the ATP analogue: triphosphates are used poorly while pentaphosphates are most efficiently processed. Notably, the novel pentaphosphate‐harbouring ATP analogue supersedes the efficiency of recently reported dual‐dye labelled analogues and thus, is a promising candidate for broad applications., Novel fluorescently labelled ATP analogues for direct monitoring of ubiquitin activation: Fluorescently modified adenosine tri‐, tetra‐ and pentaphosphates (ATP) analogues changing their fluorescence properties upon enzymatic turnover have been synthesised and applied to both E1s found in humans. Pentaphosphates were found to have superior processing and with the used acridone fluorophore the read‐out showed both fluorescence intensity and lifetime, making this assay versatile in application.

A mesomeric form of quaternary indoloquinazoline alkaloid, soyauxinium chloride (1) was obtained through the chemical investigation of stem bark and roots of Araliopsis soyauxii Engl. [syn. Vepris soyauxii (Engl.) Mziray] (Rutaceae) together with fifteen known compounds, including three furoquinoline alkaloids, three 2-quinolones, two limonoids, two triterpenes, two steroids, a coumarin, an acridone alkaloid, and a flavonoid glycoside. Their structures were established by comprehensive spectroscopic and spectrometric analyses (1D and 2D NMR, ESI-HR-MS) and by comparison with previously reported data. 13C NMR data of araliopsinine are also reported here for the first time. The isolated compounds were screened in vitro for their effects on the viability of two different human cancer cell lines, namely prostate PC-3 adenocarcinoma cells and colorectal HT-29 adenocarcinoma cells. However, none of the tested compounds exhibited strong anti-proliferative or cytotoxic activities, to either prostate PC-3 cells or colon HT-29 cells. At 100 μM, the furoquinoline maculine showed a slightly increased anti-proliferative effect, however, exclusively on HT-29 cells. The chemotaxonomic significance of the isolated compounds has also been discussed.

Amyloid-β (Aβ) and tau protein are two crucial hallmarks in Alzheimer's disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aβ and tau aggregation. In vitro studies showed that compounds 25-30 (20 μM) with N-methylation of the quinolone ring effectively inhibited Aβ1-42 aggregation by 84.7%-99.5% and tau aggregation by 71.2%-101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to Aβ1-42 and tau, inhibit Aβ1-42 β-sheets formation, and prevent tau aggregation in living cells.

DNA is the primary target of many anticancer drugs involved in important intercellular processes, especially in transcriptional regulation, and histone is known to inhibit gene expression. Small molecules can bind to histone-DNA and impair the cell division, growth, inhibition, and apoptosis in cancer cells. In this research, the interaction of a histone H1-calf thymus DNA (ct DNA) complex and propyl acridone (PA) was investigated in Tris-HCl buffer, pH 6.8, using multi-spectroscopic, viscosity, and molecular modeling techniques. The Stern Volmer plot of the (H1-ct DNA) PA complex demonstrated two sets of binding sites with various binding affinities at three different temperatures. Thermodynamic parameters (ΔH° 0 and ΔS° 0) indicated that hydrogen bonds and van der Waals forces played the main roles in the binding of the drug to H1-ct DNA. The interaction between PA and ct DNA as well as (H1-ct-DNA) in the presence of acridine orange and ethidium bromide showed two different interaction behaviors in ternary systems. According to results from UV absorption spectroscopy and melting temperature (Tm) measurements, the binding mode of PA with ct DNA and the (H1-ct DNA) complex was indicative of an intercalative binding for the binary system and of both intercalative with groove binding with molecular fraction for the ternary system. Furthermore, the PA-induced detectable changes in the circular dichroism spectrum of ct DNA as well as changes in its viscosity. All of the experimental results proved that the intercalative binding between PA and ct DNA as well as the (H1-ct DNA) complex as binary and ternary systems must be predominant. The results obtained from experimental data were in good agreement with molecular modeling with regard to the determination of the binding site of PA to ct DNA in the absence and presence of histone H1.

Quinolone synthase from Aegle marmelos (AmQNS) is a Rutacean-specific plant type III polyketide synthase that synthesizes quinolone, acridone, and benzalacetone with therapeutic potential. Simple architecture and broad substrate affinity of AmQNS make it as one of the target enzymes to produce novel structural scaffolds. Another unique feature of AmQNS despite its high similarity to acridone forming type III polyketide synthase from Citrus microcarpa is the variation in the product formation. Hence, to explore the characteristic features of AmQNS, an in-depth sequence and structure-based bioinformatics analyses were performed. Our studies indicated that AmQNS and its nearest homologs have evolved by a series of gene duplication events and strong purifying selection pressure constrains them in the evolutionary process. Additionally, some amino acid alterations were identified in the functionally important region(s), which can contribute to the functional divergence of the enzyme. Prediction of favorable amino acid substitutions will be advantageous in the metabolic engineering of AmQNS for the production of novel compounds. Furthermore, comparative modeling and docking studies were utilized to investigate the structural behavior and small molecule interaction pattern of AmQNS. The observations and results reported here are crucial for advancing our understanding of AmQNS's phylogenetic position, selection pressure, evolvability, interaction pattern and thus providing the foundation for further studies on the structural and reaction mechanism.

In continuation of our efforts to develop new drugs with antibacterial properties we have synthesized and evaluated new 1,2,3-triazole derivatives from acridone. The synthetic approach was started by the preparation of acridone skeleton through the Ullman condensation of 2-bromobenzoic acid and aniline derivatives. Subsequently, acridone nucleus was functionalized with propargyl bromide. Then, a click reaction of the latter compound and aromatic azides led to the formation of the title compounds in good yields. The synthesized compounds were screened for their in vitro antibacterial activity against one gram-positive bacteria S. aureus and three gram-negative bacteria P. putida, K. pneumoniae and E. coli. Among the synthesized compounds, 2-methyl-10-((1-(o-tolyl)-1H-1,2,3-triazol-4-yl)methyl)acridone (4e) had the most potent inhibitory activity against S. aureus with MIC = 10.1 µg/mL. Then, in silico docking studies were used in order to understand the binding interactions and mode of action of these compounds.

Currently, organic artificial enzymes as biocatalysts have been extensively used to construct various colorimetric sensors. However, exploiting a potential organic artificial enzyme with high catalytic efficiency still remains a challenge. To address this issue, herein, we synthesize an acridone derivative 10-benzyl-2-amino-acridone (BAA). The synthesized BAA exhibits an intrinsic visible-light-stimulated oxidase-like activity, which is capable of oxidizing various chromogenic substrates without destructive hydrogen peroxide (H2O2) under visible light stimulation, resulting in colored products. The reaction system can be regulated by switching light on and off, which is milder and more reliable means than others H2O2-dependent. The photocatalytic mechanism of BAA is investigated in detail. However, l -ascorbic acid (AA), an antioxidant generating from the acid phosphatase (ACP)-mediated hydrolysis of 2-phospho- l -ascorbic acid (AAP), is able to inhibit the catalytic activity of BAA. Based on the above properties, a facile, photo-switchable and low-cost colorimetric sensing strategy is developed for ACP detection. The linear range is 0.05–2.5 U/L (r = 0.9994), and the limit of detection (LOD) is 0.0415 U/L. Moreover, the proposed sensing system can be applied for monitoring ACP activity in practical samples, demonstrating promising applications in clinical analysis and biosensor platform.

Intramolecular cyclization of N-aryl-2-[(9-oxoacridin-10(9H)-yl)acetyl]hydrazinecarboxamides afforded new 10-(5-arylamino-1,3,4-oxadiazol-2-ylmethyl)acridin-9(10H)-ones. Some of the synthesized compounds showed a moderate antimicrobial activity against gram-positive and gram-negative bacteria. Keywords: acridone, hydrazide, semicarbazide, 1,3,4-oxadiazole, antibacterial activity

Chemical investigation of root bark of Glycosmis pentaphylla and stem bark of Tabernaemontana coronaria led to the isolation of three carbazole alkaloids glycozoline, glycozolidine and methyl carbazole 3-carboxylate, two furoquinoline alkaloids skimmianine and dictamine, an acridone alkaloid arborinine, three monomeric indole alkaloids coronaridine, 10-methoxy coronaridine and tabernaemontanine, and two dimeric indole alkaloids voacamine and tabernaelegantine B. Their structures were established by detailed spectral analysis. Mutagenic and antimutagenic potential of methanol extract of both plant materials were evaluated by Ames test against known positive mutagens 2-aminofluorine, 4-nitro-O-phenylenediamine and sodium azide using Salmonella typhimurium TA 98 and TA 100 bacterial strains both in the presence and absence of S9. Both the extracts were non-mutagenic in nature. Both the extracts of G. pentaphylla and T. coronaria exhibited significant antimutagenic activity against NPD and sodium azide for S. typhimurium TA98 and TA100 strains. The results indicated that the extracts could counteract the mutagenicity induced by different genotoxic compounds.

Two new acridone alkaloids, verdoocridone A (1) and B (4), together with fifteen known compounds were isolated from methanol extracts of the roots and leaves of Vepris verdoorniana. The structures of all compounds were determined by comprehensive spectroscopic analyses (1D and 2D NMR, EI-and ESIMS). The C-13 NMR values of 1,2,3,5-tetramethoxy-N-methylacridone (2) and 5-methoxyaborinine (3) are also reported. The crude extracts and compounds (1-6) were tested for their antimicrobial activity. The test delivered moderate activities for crude extracts and compounds 1, 5 and 6 against the bacterium Staphylococcus aureus and the fungi Mucor meihei and Candida albicans with MIC values between 115 and 180 mu g/mL for extracts and between 21.3 and 29.4 mu M for compounds, compared to gentamycin with 0.2 mu M and nystatin with 5.2 mu M against both fungi. The determination of the radical scanvenging activity using 1,1-dephenyl-2-picrylhydrazyl (DPPH) assay gave moderate antioxidant values for all tested compounds, with IC50 between 0.29 and 0.41 mu M, compared to the standard 3-t-butyl-4hydroxyanisole (BHA) displaying 0.03 mu M. (C) 2017 Phytochemical Society of Europe. Published by Elsevier Ltd. All rights reserved.

Hybrid systems of acridones with substituted pyrimidines were designed with an objective of discovering next generation anticancer agents targeting multiple mechanisms in the cancer cell. Hybrid compounds were synthesized by simple and convenient methods in the lab, characterized by NMR and Mass spectral methods and screened for cytotoxicity against A549 (lung), Hela (cervical), MCF7 (breast) and MDA-MB-231 (breast) cancer cell lines respectively. Evaluation of compounds for cell proliferation identified active compounds 11b, 11d and 11h against MCF7, MDA-MB-231 and A549 cell lines. Further absorption titrations with CT-DNA and gel electrophoresis identified that hybrid molecules displayed anticancer activity partly by DNA intercalation. Also further results of western blotting assay with Akt kinase identified that hybrid compounds have the ability to inhibit the Akt kinase activity and induce apoptosis, with ABCC1 suggests that active compounds too have the ability to modulate multidrug resistance (MDR) associated with ABCC1/MRP1. Selective Akt1 kinase assay have identified 11a, 11b, 11d and 11h as potential inhibitors. Molecular docking studies identified the orientation and binding interactions at the active site of Akt1 and DNA. Compounds 12e and 12f have shown good cytotoxicity profile against lung cancer cell lines of sensitive and resistant type. Acute toxicity study of compound 12f at the dose of 5000 mg/kg has identified no signs of clinical toxicity. Prediction of ADMET properties and oral toxicity of the drug likeness features of new hybrid systems were carried out using software's. This experimental data suggests that hybrid systems of acridone with substituted pyrimidines can be taken as a lead for the design of efficient inhibitors and active compounds which can be taken up for further studies.

Spectroscopic and docking analyses reveal that acridone (AD) interacts with both the tryptophan (Trp) residues of bovine serum albumin (BSA) (both Trp 134 and Trp 212) in contrast to other organic ligands including other acridine derivatives which generally prefer to interact with Trp 212. The use of fluorescence spectroscopy, specifically the unusual time-resolved area normalized spectra depicting two isoemissive points with different times of evolution, confirms that AD “unusually” interacts with both the Trp residues present in the model protein. Upward curvature of the Stern Volmer plot suggests the interaction of AD with both the Trp residues present in varying microenvironments within BSA and possibly also indicates the denaturation of the protein. Ground state interaction of AD and BSA is explored using absorption spectroscopy, whereas strong perturbation in secondary and tertiary structures of the model protein on binding with the ligand is divulged from the observation of circular dichroism spectroscopy. Femtosecond fluorescence up-conversion kinetics implies that a photoinduced electron transfer reaction takes place from the Trp residue of the protein to AD, which has been authenticated using laser flash photolysis via identification of the radical ions. Binding as well as thermodynamic parameters associated with AD–BSA interaction are obtained from fluorescence studies. The prime deduction from the detailed spectroscopic and docking analyses is that AD initially interacts with Trp 212 present in the crevice of hydrophobic domain IIA of the protein and then perturbs the structure of BSA to bring about conformational changes such that it can gain access to Trp 134 housed in hydrophilic domain IB, which is possibly facilitated by hydrogen bonding.

During the course of our studies towards the identification of promising chemotherapeutic candidates from plants against two human T-cell lymphotropic virus type I-infected T-cell lines (MT-1 and MT-2), we screened 17 extracts from 9 rutaceous plants against MT-1 and MT-2 cells. The extracts from the aerial parts and roots of Boenninghausenia japonica, as well as the leaves and roots of Ruta graveolens showed potent antiproliferative effects. After activity-guided fractionation, we isolated 44 compounds from two rutaceous plants, including three new compounds (1-3), which were classified into 26 coumarin analogs (13 coumarins, 8 furanocoumarins, 4 dihydrofuranocoumarins and one dihydropyranocoumarin), 15 alkaloid analogs (7 quinolone alkaloids, 4 acridone alkaloids, 3 furanoquinoline alkaloids and one tetrahydroacridone alkaloid) and 3 flavonoid glycosides. Structure-activity relationship studies were also evaluated. The coumarin compounds (2, 3 and 7-9) bearing a 3-dimethylallyl moiety showed potent activity. Similarly, of all the furanocoumarins evaluated in the current study, compound 17 bearing a 3-dimethylallyl group also showed potent activity. A dihydrofuranocoumarin (27) bearing a 3-dimethylallyl moiety showed the most potent activity. Following 27, compound 28 showed potent activity. These results therefore suggested that the presence of a 3-dimethylallyl moiety was important to the antiproliferative activity of these coumarin analogs.

A series of novel acridones bearing a 1,2,3-triazole unit have been synthesized and characterized. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was performed using both a conventional method and a microwave-assisted synthetic method. The in vitro antibacterial potencies of all the synthesized compounds were determined against five clinically isolated strains: Escherichia coli, Klebsiella pneumonia, Pseudomonas putida, Serratia marcescens and Staphyloccocus aureus. Furthermore, DFT quantum chemical calculations were carried out to investigate geometry structures, frontier molecular orbital and gap energies, and molecular electrostatic potential maps (MEP). Lipophilicities of the studied compounds were also determined. Novel acridone-1,2,3-triazole derivatives were synthesized using both a conventional and a microwave-assisted synthetic method. The antibacterial potencies of the compounds are reported. DFT quantum chemical calculations were carried out to investigate geometry structures, frontier molecular orbital and gap energies, and molecular electro static potential maps (MEP). Lipophilicities were also determined.

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

Aim The increase in the number of fungal infections worldwide, coupled with the limitations of current antifungal chemotherapy, demand the development of safe and effective new antifungals. Here, we presented the synthesis of a novel acridone (M14) and its antifungal properties against Candida and dermatophytes species. Methods and results A series of 17 acridones was designed, synthesized and tested for its antifungal activity. The minimum inhibitory concentration (MIC) was determined by the broth microdilution method. Only the acridone M14 showed growth-inhibitory activity against reference strains and clinical isolates of Candida and dermatophytes, with MIC range of 7·81-31·25 µg ml-1 . Moreover, M14 exhibited fungicidal activity and prevented biofilm formation by C. albicans as well as reduced the viability of preformed biofilms, even at sub-MICs. The confocal laser scanning microscopy analysis revealed that C. albicans hyphal growth was completely inhibited in the presence of M14. Similarly, there was a severe inhibition on hyphal growth of Trichophyton rubrum. We also found that M14 has relatively low toxicity to human fibroblasts. Conclusions The new acridone M14 has antifungal properties against Candida spp. and dermatophytes, and antibiofilm activity against C. albicans. In addition, M14 is relatively selective to fungal cells compared to human normal cells. Significance and impact of the study Because of its in vitro antifungal activity, anti-Candida biofilm effect and moderate cytotoxicity towards normal human cell, M14 may serve as a valuable lead compound to develop a new antifungal agent.

The ethyl acetate extract of the rhizomes of Luvunga scandens (Roxb.) Buch. - Ham. ex Wight & Arn (Rutaceae) delivered one new acridone alkaloid named Luvungaside A (1) together with three known ac...

Arborinine is an acridone alkaloids obtained from different natural sources including in the majority bark, seed, leaves of plants species of Rutaceae family among which Teclea gerrardii, Zanthoxylum leprieurii and Teclea trichocarpa, Erthela bahiensis, Ruta angustifolia,, Ruta suavolenses.. This alkaloid is extensively studied due to its great pharmacological potential, which includes anticancer, antimicrobial, antiparasitic, antifeedant and antioxidant activities among others. Arborinine block heme-mediated protein oxidation and degradation markers for heme-induced oxidative stress; was predicted virtually for a critical evaluation by In silico target fishing for rationalized ligand discovery by inhibiting acetylchlolinesterase with IC50 value 34.7 ± 71µM; displayed potent in vitro activities against chloroquine sensitive HB3 cell line and chloroquine resistance K1 cell line with IC50 value 3.85 ± 0.11μM and 9.34 ± 0.37 μM; showed the good anticancer activity on three human cancer line viz human colon cancer COLO-205, human ovarian cancer OVCAR-3, Human cervical cancer human breast cancer and T-47D line with GI50 value ˂10μg/ml and presented antimicrobial activities against resistant microbial strains. The overall synthesis of Arborinine has been done and the key stapes are the Ullmann condensation followed by the cyclisation with Eaton’s reagent. It undergoes a few structural modification reactions such as selective methylation and demethylation, electrophilic substitution. Acetylation, benzoylation. This review present the chemistry and the biological properties of Arborinine: methods of isolation from plant crude extract, its characterization as well as their derivatives obtained by structural modification including structure activity relationship are also described.

The present study was carried out in an attempt to synthesize a new class of potential antibacterial agents. In this context, novel isoxazoles were synthesized and evaluated for their potential antibacterial behavior against four pathogenic bacterial strains. The synthesized compounds exhibited moderate-to-good antibacterial activity against these strains. The highest antibacterial activity was observed against the Escherichia coli strains, particularly for compounds 4a and 4e with phenyl and para-nitrophenyl groups on the isoxazole-acridone skeleton; they showed promising minimum inhibitory concentration values of 16.88 and 19.01 μg/ml, respectively, compared with the standard drug chloramphenicol (22.41 µg/ml). The synthesized compounds were subjected to in silico docking studies to understand the mode of their interactions with the DNA topoisomerase complex (PDB ID: 3FV5) of E. coli. The molecular docking results showed that compounds 4a-l occupy the active site of DNA topoisomerase (PDB ID: 3FV5), stabilized via hydrogen bonding and hydrophobic interactions, which may be the reason behind their interesting in vitro antibacterial activity.

Two new alkaloids, poggeicridone (1) and 2-methoxy-7,8- dehydroruteacarpine (6), together with nine known compounds, were isolated from the dichloromethane (DCM) extract of the bark of Zanthoxylum poggei (Engl.) P. G. Waterman. The structures of all compounds were determined by comprehensive spectroscopic analyses (1D and 2D NMR and EI- and ESI–MS). Compounds 5-9 exhibited strong suppressive effects on the phagocytosis response upon activation with serum opsonized zymosan in the in vitro oxidative burst studies using whole blood. The IC50 values were in the range of 12.0–25.9 μM. These compounds displayed a moderate level of cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC50 values of 15.8 and 22.1 μM (the IC50 value of the positive control standard doxorubicin was IC50 0.9 μM). All isolated compounds were also tested against plant pathogenic bacteria, fungi and oomycetes using the paper disk agar diffusion assay, resulting in no significant activities (MICs > 1 mg/mL). © 2016 Phytochemical Society of Europe

A newly synthesized acridone derivative 8a shows potent antitumor activity against CCRF-CEM leukemia cells. Herein, the first proteomic study of 8a effects in CCRF-CEM cells was performed by 2D nano-LC-ESI-MS/MS to better understand the mechanisms of action of 8a. Data analyses based on PLGS, STRING, Cytoscape, and database for annotation, visualization, and integrated discovery identified 55 proteins that were differentially expressed in response to 8a exposure. Multiple cellular pathways were affected, including chromatin organization, energy metabolism, DNA repair, oxidative-stress, and apoptosis. The changes in protein expression were further verified for PKM2. Moreover, 8a lowered down the expression of HEX and PFK-1. Lactate production was decreased in 8a-treated cells, indicating suppression of glycolysis. The elevated XRCC6 and decreased histone expression levels suggested increased DNA damage in 8a-treated cells, which was confirmed by the increased γ-H2AX foci. Molecular docking of 8a with DNA demonstrated direct interactions of 8a with DNA through three hydrogen bonds and four π-π interactions, potentially explaining the mode of action that 8a damaged to DNA. The differential protein profiling and dysfunction of metabolic pathways induced by 8a provide novel insights into the potential action mechanisms of 8a.

Carbamazepine (CBZ) is one of the most recalcitrant pharmaceutically active compounds routinely detected in wastewater effluent-impacted environment. Biocatalytic degradation with enzymes such as laccase provides a promising approach for the elimination of CBZ. However, the relatively low redox potential of laccase makes its efficient CBZ degradation difficult. Therefore, an environmentally benign and effective mediator is required. In this study, three natural phenolic compounds, namely p-coumaric acid (PCA), syringaldehyde (SYR), and acetosyringone (ACE), were investigated as redox mediators for the enzymatic removal of CBZ by both free and immobilized laccase. Among the tested mediators, PCA resulted in the optimal CBZ removal performance with 60% removal rate (20 μM initial CBZ) after 96 h incubation with immobilized laccase in a conventional suspension system. The degradation of CBZ was then carried out in a membrane hybrid reactor with the effluent recirculating through suspended biocatalytic TiO 2 nanoparticles. The effect of operation parameters including PCA concentrations, initial enzyme activity and operational flux on CBZ removal were investigated. Further CBZ metabolites study identified 10,11-dihydro-10,11-dihydroxy-CBZ (CBZD), 10,11-dihydro-10,11-epoxy-CBZ (CBZE) and acridone as the major metabolites of CBZ oxidation by laccase. The toxicity tests determined by algal viability using the fluorometric indicator alamarBlue indicated that the CBZ treatment via the hybrid reactor could effectively remove the toxicity of parent CBZ compound.

Sulfide plays an important role in many important life processes, and abnormal levels of sulfide that may cause diseases. Sulfide is also essential in industrial production and food processing, and it is well concerned for environmental issues and food safety. In order to study the physiological and pathological effects of sulfide and the impact on the environment, it is still urgent to develop a convenient and effective sulfide detection technology. Here, we developed a ratiometric fluorescent probe 7-Nitro-1,2,3-benzoxoxadiazole-Acridoneacetylpiperazine (NBD-AAP) which is based on the fluorescence resonance energy transfer (FRET) between acridone and NBD fluorophores. The NBD-AAP probe could produce a ratiometric response to micromolar sulfide in buffer (pH = 7.4), exhibiting a significant enhancement in fluorescent emission ratio (F427/F552) and obvious visual phenomenon (orange to pink under visible light and yellow to blue under UV light). At the same time, this NBD-AAP probe also has excellent properties including high selectivity and low detection limit (0.19 μM). In addition, this probe has been successfully used for detecting the sulfide in actual samples (monosodium glutamate, beer, environmental water) and imaging in Daphnia magna. These results indicate that NBD-AAP has broad application prospects in sulfide detection and in vivo imaging studies.

'Acridine' along with its functional analogue 'Acridone' is the most privileged pharmacophore in medicinal chemistry with diverse applications ranging from DNA intercalators, endonuclease mimics, ratiometric selective ion sensors, and P-glycoprotein inhibitors in countering the multi-drug resistance, enzyme inhibitors, and reversals of neurodegenerative disorders. Their interaction with DNA and ability of selectively identifying numerous biologically useful ions has cemented exploitability of the acridone nucleus in modern day therapeutics. Additionally, most derivatives and salts of acridine are planar, crystalline, and stable displaying a strong fluorescence which, when coupled with their marked bio selectivity and low cytotoxicity, enables the studying and monitoring of several biochemical, metabolic, and pharmacological processes. In this review, a detailed picture covering the important therapeutic aspects of the acridone nucleus and its functional analogues is discussed.

Targeting dihydrofolate reductase, here, we report the tumor growth inhibitory activity of substituted acridones. The screening of the molecules over 60 cell line panel of human cancer cells identified (S)-oxiran-2-ylmethyl 9-oxo-9,10-dihydroacridine-4-carboxylate (19) with average GI50 0.3 μM. The specificity of the compound to CCRF-CEM, MOLT-4 and SR cell lines of leukemia and SW-620, SF268, LOXIMVI, ACHN and MCF7 cancerous cells exhibiting GI50 in the nM range was observed. C6 Glioma cells treated with compound 19 showed differentiated cell morphology and cell cycle arrest in G2/M phase. The interactions of the compound with dihydrofolate reductase were ascertained with the help of enzyme immunoassays, molecular docking and molecular dynamic studies.

Ethnopharmacological relevance: Citrus aurantium L. (Rutaceae) is used, either singly or as a part of a polyherbal preparation, in Nigerian traditional medicine for the management of cancer and inflammatory diseases. Currently, there is a dearth of knowledge demonstrating its anticancer potential.\ud Aim of the study: This study was carried out to determine the in vitro cytotoxicity of the crude extract of the stem bark of C. aurantium, identify and isolate the bioactive constituents and to establish the cytotoxicity of such constituents.\ud Material and Methods The powdered bark of C. aurantium was extracted with methanol at room temperature (25-34 °C) and the crude extract was partitioned successively, with nhexane, dichloromethane (DCM) and methanol. Amongst the fractions, the DCM fraction was the most active and compounds were isolated from this fraction using several chromatographic techniques. The structures of the isolated compounds were elucidated by spectroscopic means (mass spectrometry, one-dimensional and two-dimensional nuclear magnetic resonance). The cytotoxicity of the extract, and the isolated compounds were evaluated by the MTT (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium) assay against four human cancer cell lines: A549 (lung), HepG2 (liver), MCF7 (breast) and PC3 (prostate). The selectivity of the isolated compounds was assessed using the normal human prostate epithelium cells (PNT2).\ud Results and Discussion: Of the three plant fractions, the DCM fraction showed significant cytotoxicity, with its highest activity against A549 cells (IC50 = 3.88 µg/mL) and the least activity on HepG2 cells (IC50 = 5.73 µg/mL). Six acridone alkaloids: citrusinine-I (1), citracridone-I (2), 5-hydroxynoracronycine (3), natsucitrine-I (4), glycofolinine (5) and citracridone-III (6), were isolated from the DCM fraction of C. aurantium. The isolated compounds demonstrated potent to moderate cytotoxicity ((IC50 = 12.65 – 50.74 µM) against the cancer cells under investigation. It is noteworthy that the compounds exerted cytotoxicity at least four times more selective towards the carcinoma cells than the PNT2 cells.\ud Conclusion: The results obtained from this study have provided some evidence for the ethnomedicinal use of C. aurantium against cancer and the acridone alkaloids present in its stem bark, have appeared to be responsible for this effect. Further research to explore the underlying molecular mechanism of the isolated acridone alkaloids is needful.

Glycosmis parva is a small shrub found in Thailand. Ethyl acetate (EtOAc) extract from its leaves has been shown to exert anticancer effects in vitro; however, the compound responsible for this activity has not been isolated and characterized. In this study, we demonstrate that arborinine, a major acridone alkaloid in the EtOAc fraction, decreased proliferation and was strongly cytotoxic to HeLa cervical cancer cells without significantly affecting normal cells. The compound also inhibited tumor spheroid growth much more potently than chemotherapeutic drugs bleomycin, gemcitabine, and cisplatin. In addition, unlike cisplatin, arborinine activated caspase-dependent apoptosis without inducing DNA damage response. We further show that arborinine strongly suppressed cancer cell migration by downregulating expression of key regulators of epithelial-mesenchymal transition. Taken together, our data provide important insights into the molecular mechanism of arborinine’s anticancer activity, supporting its potential use for treating cervical cancer.

In the past decades, the tricyclic acridone ring system has become a focus of major research by medicinal chemists due to the biological significance of this moiety in drug design and discovery. Acridone has substantial bio-potential since it performs crucial functions, including antibacterial, antimalarial, antiviral and anti-neoplastic activities. However, the anticancer effect and the underlying mechanisms of acridone on breast cancer cells remains unclear. In the present study, the anti-tumor function and the underlying mechanisms of acridone were evaluated in vitro. Firstly, an MTT assay was used to evaluate the inhibitory effect of acridone. Subsequently, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to investigate whether ATP binding cassette subfamily G member 2 (ABCG2) was associated with the function of acridone. Finally, western blotting was used to confirm the results of RT-qPCR. The present study demonstrated that acridone may decrease the proliferation of MDA-MB-231 cells dose-dependently. Further experiments revealed that acridone may downregulate the mRNA and protein expression levels of ABCG2, supporting the potential application of acridone in breast cancer treatment. These findings suggested that acridone is a potential agent in the treatment of human breast cancer.

Introduction Chemotherapy is one of the preferred mode of treatment of malignancies, but is complicated by the expression of diverse resistance mechanisms of cancer cells. Methods In the present study, we investigated the cytotoxicity of five alkaloids including a furoquinoline montrofoline (1) and four acridones namely 1-hydroxy-4-methoxy-10-methylacridone (2), norevoxanthine (3), evoxanthine (4), 1,3-dimethoxy-10-methylacridone (5) against 9 drug-sensitive and multidrug-resistant (MDR) cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analyzed via flow cytometry. Results Furoquinoline 1 as well as the acridone alkaloids 2–5 displayed cytotoxic effects with IC50 values below 138 µM on all the 9 tested cancer cell lines. The IC50 values ranged from 41.56 µM (towards hepatocarinoma HepG2 cells) to 90.66 µM [towards colon carcinoma HCT116 (p53−/−) cells] for 1, from 6.78 µM [towards HCT116 (p53−/−) cells) to 106.47 µM [towards breast adenocarcinoma MDA-MB-231-pcDNA cells] for 2, from 5.72 µM (towards gliobastoma U87MG.ΔEGFR cells) to 137.62 µM (towards leukemia CCRF-CEM cells] for 3, from 6.11 µM [towards HCT116 (p53+/+) cells] to 80.99 µM (towards HepG2 cells] for 4, from 3.38 µM (towards MDA-MB-231-BCRP cells) to 58.10 µM (towards leukemia CEM/ADR5000 cells] for 5 and from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (against CEM/ADR5000 cells) for doxorubicin. Acridone alkaloid 5 induced apoptosis in CCRF-CEM leukemia cells, mediated by increased ROS production. Conclusions The five tested alkaloids and mostly acridone 5 are potential cytotoxic natural products that deserve more investigations to develop novel cytotoxic compounds against multifactorial drug-resistant cancers.

In the past decades, tricyclic acridone ring system has become one of the major research interests of the medicinal chemists due to the biological significance of this moiety in drug design and drug discovery. Acridone scaffold has substantial bio-potential since it possess crucial activities such as antibacterial, antimalarial, antiviral and anti-neoplastic. The diverse biological activity of acridone and its prospective in reversal of multi-drug resistance has attracted attention of medicinal chemists to explore this scaffold especially to treat multi-drug resistance in cancer. Considering this potential in this review we have summarized the synthesis and the antitumor activities of different acridone derived compounds reported from 2000 to 2014.

An acridone based highly Zn2+ selective, cell-permeable turn-on fluorescence probe (AAS) shows yellow fluorescence at 560 nm (λex, 445 nm) in dry methanol/DMSO up to 100 μM Zn2+. At higher Zn2+ concentration (>100 μM in dry methanol) AAS yields a red solid polymeric complex having strong emission at 605 nm. Interestingly, the red solid polymer also appears at relatively lower Zn2+ concentration (>50 μM) in water. The lowest detection limit of AAS is 0.1 nM Zn2+. AAS is employed for fluorescence bio-imaging of Zn2+ in human MCF 7 breast cancer cells and HeLa cells. Moreover, AAS develops an orange colour detectable by the naked eye in the presence of trace Zn2+ in a mixture of various common cations and anions in the solid state (requires no solvent). Hence, this method is extremely green and interference free. AAS can be employed as a laboratory indicator for detection of Zn2+ in real samples and live cells.

Isolation, characterization and anti-Toxoplasma gondii activity of constituents from the CH2Cl2/MeOH (1/1) extract of the roots of the cameroonian plant Balsamocitrus camerunensis L. were investigated in this study. Four known coumarins derivatives were isolated, namely, marmin (1), imperatorin (2), xanthoxyletin (3), 6,7-Dimethoxycoumarin (4) and an acridone derivative namely 1-hydroxy-3-methoxy-acridone (5). Their structures were established on the basis of their spectroscopic data compared to reported results. Some of the isolated compounds showed noteworthy activity against Toxoplasma gondii intracellular parasite in mammals with an inhibition of parasite growth of around 46.44% for compound 4 and 82.12% for compound 3 which was the most active compound.Keywords: Balsamocitrus camerunensis, Rutaceae, coumarins, alkaloid, toxoplasmacidial activity.African Journal of Biotechnology, Vol 13(52) 4680-4684

A new prenylated acridone alkaloid, medicacridone (1), and a new ferulate xanthone, medicaxanthone (5), together with 11 known compounds were isolated from the methanol extract of the bark of the Cameroonian medicinal plant Citrus medica. The structures of all compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data, chemical reactions, and comparison with previously known analogues. The agar diffusion test delivered low to missing antimicrobial activities, corresponding with MICs > 1 mg mL–1, while compounds 1–6 and atalantoflavone (9) displayed weak cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC50 values ranging from 60.5 to 80.0 μm versus doxorubicine with IC50=0.9 μm.

In a quest for finding potent cytotoxic molecules, we have designed and synthesized a new scaffold by tagging quinazolinones with an acridone moiety. The new acridone-4-carboximide derivatives were evaluated for their cytotoxic potentials against the MCF7 breast cancer cell line and three colon cancer cell lines (LS174T, SW1398, and WiDr). Compound 26 showed relatively potent cytotoxic activity among the derivatives, against all the cell lines tested. Mechanistic studies for the selected derivatives 7, 8, 16, 17, 25, and 26 were conducted through in vitro EGFR tyrosine kinase inhibition studies. The results indicate that compound 26 has a better EGFR tyrosine kinase inhibitory profile. The in vitro EGFR inhibition data was correlated with the cytotoxic properties, and molecular docking studies were performed with regard to the receptor autophosphorylation sites of the protein kinase domain of the EGFR.

Vitiligo progression is attributed to immune system malfunctioning, thus immunomodulating compounds might be beneficial in stopping vitiligo progression which is a prerequisite for successful repigmentation. The goal of this study was to assess efficacy of acridone acetic acid, sodium salt (Na-AAA), an immunomodulating compound with favorable safety profile, in stabilizing active vitiligo, and to reveal prognostic factors of treatment outcome. Sixty consecutive patients with progressing nonsegmental vitiligo were treated with 10 i.m. injections of Na-AAA every other day. Disease stability was assessed in 1, 3, 6, and 12 months post-treatment. Statistical analysis was applied to correlate treatment outcome and available clinical parameters. Of the 60 patients treated, vitiligo stopped progression in 44 patients (73.3%). Older age (p = 0.0219), age of 35 and older (p = 0.0189, odds ratio (OR) = 5.2, 95% confidence interval (CI) 1.30-20.84) or age of 40 and older (p = 0.0039, OR = 6.48, 95% CI 1.86-22.61), longer disease duration (p = 0.0234), pre-treatment interleukin-6 level over 2 pg/mL (p = 0.0005, OR = 13.7, 95% CI 2.97-63), and over the reference threshold value 5.9 pg/mL (p = 0.0009, OR = 25.8, 95% CI 2.8-239) as well as presence of other autoimmune diseases (p = 0.038, OR = 7.0, 95% CI 1.14-42.97) were negative prognostic factors of treatment success. In conclusion, acridone acetic acid, sodium salt, emerges as an efficient option for stopping vitiligo progression.

The anticancer activity of acridone derivatives has attracted increasing interest, therefore, a variety of substituted analogs belonging to this family have been developed and evaluated for their anti-cancer properties. A series of N-alkyl-acridones 1&ndash, 6 and N,N&prime, dialkyl-9,9&prime, biacridylidenes 7&ndash, 12 with variable alkyl chains were examined for their topoisomerase I activity at neutral and acidic conditions as well as for their binding capacity to calf thymus and possible radical trapping antioxidant activity. It was found that at a neutral pH, topoisomerase I activity of both classes of compounds was similar, while under acidic conditions, enhanced intercalation was observed. N-alkyl-acridone derivatives 1&ndash, 6 exhibited stronger, dose-dependent, cytotoxic activity against MCF-7 human breast epithelial cancer cells than N,N&prime, 12, revealing that conjugation of the heteroaromatic system plays a significant role on the effective distribution of the compound in the intracellular environment. Cellular investigation of long alkyl derivatives against cell migration exhibited 40&ndash, 50% wound healing effects and cytoplasm diffusion, while compounds with shorter alkyl chains were accumulated both in the nucleus and cytoplasm. All N,N&prime, biacridylidenes showed unexpected high scavenging activity towards DPPH or ABTS radicals which may be explained by higher stabilization of radical cations by the extended conjugation of heteroaromatic ring system.