Riminophenazine Derivatives as Potential Antituberculosis Agents: Synthesis, Biological, and Electrochemical Evaluations.

A series of novel riminophenazine derivatives, having ionizable alkyl substituents at N-5 and a variety of substituents on the C-3 imino nitrogen, at C-8 and on the pendant aryl group, have been designed and synthesized. Preliminary investigations into the relationship between lipophilicity, redox potential, and antimycobacterial activity were conducted, using the in vitro activity against Mycobacterium tuberculosis H37Rv, mammalian cytotoxicity, and the redox potential of the compounds determined by cyclic voltammetry as measures. Results revealed an activity "cliff" associated with C-8 substitution (10l and 10m) that, along with defined redox activity, point to a new class of riminophenazines as potential anti-tuberculosis agents having reasonable activity (MIC99 ~1 µM).

ß-Hydroxy sulfides and their syntheses.

Sulfur-containing natural products are ubiquitous in nature, their most abundant source being marine organisms since sulfur, in the form of the sulfate ion, is the second most abundant anion in sea water after chloride. As part of natural products, sulfur can appear in a multitude of combinations and oxidation states: thiol, sulfide (acyclic or heterocyclic), disulfide, sulfoxide, sulfonate, thioaminal, hemithioacetal, various thioesters, thiocarbamate and isothiocyanate. This review article focuses on ß-hydroxy sulfides and analogs; their presence in natural products, general protocols for their synthesis, and examples of their application in target oriented synthesis.

Design, synthesis, and In vitro antituberculosis activity of 2(5H)-Furanone derivatives.

A series of 2(5H)-furanone-based compounds were synthesized from commercially available mucohalic acids. From the first-generation compounds, three showed inhibitory activity (10 µg/mL) of at least 35% against Mycobacterium smegmatis mc(2) 155 growth (Bioscreen C system). In screening the active first-generation compounds for growth inhibition against Mycobacterium tuberculosis H37Rv, the most active compound was identified with a minimum inhibitory concentration (MIC99 ) of 8.07 µg/mL (15.8 µM) using BACTEC 460 system. No cross-resistance was observed with some current first-line anti-TB drugs, since it similarly inhibited the growth of multidrug resistant (MDR) clinical isolates. The compound showed a good selectivity for mycobacteria since it did not inhibit the growth of selected Gram-positive and Gram-negative bacteria. It also showed synergistic activity with rifampicin (RIF) and additive activity with isoniazid (INH) and ethambutol (EMB). Additional time-kill studies showed that the compound is bacteriostatic to mycobacteria, but cytotoxic to the Chinese Hamster Ovarian (CHO) cell line. From a second generation library, two compounds showed improved anti-TB activity against M. tuberculosis H37Rv and decreased CHO cell cytotoxicity. The compounds exhibited MIC values of 2.62 µg/mL (5.6 µM) and 3.07 µg/mL (5.6 µM) respectively. The improved cytotoxicity against CHO cell line of the two compounds ranged from IC50 = 38.24 µg/mL to IC50 = 45.58 µg/mL when compared to the most active first-generation compound (IC50 = 1.82 µg/mL). The two second generation leads with selectivity indices (SI) of 14.64 and 14.85 respectively, warrant further development as anti-TB drug candidates. © 2016 IUBMB Life, 68(8):612-620, 2016.

Correction: A convenient domino Ferrier rearrangement-intramolecular cyclization for the synthesis of novel benzopyran-fused pyranoquinolines.

Correction for 'A convenient domino Ferrier rearrangement-intramolecular cyclization for the synthesis of novel benzopyran-fused pyranoquinolines' by Paseka T. Moshapo et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c5ob02536b.

A convenient domino Ferrier rearrangement-intramolecular cyclization for the synthesis of novel benzopyran-fused pyranoquinolines.

The Ferrier rearrangement and the Povarov reaction have proven indispensable tools in carbohydrate chemistry and the synthesis of N-heterocycles, respectively. We hereby report a one-pot cyclization sequence involving the Ferrier and Povarov-like reactions in the synthesis of novel pentacyclic N-heterocycles: benzopyran-fused pyranoquinolines. The reaction entails three component condensation of a glycal with a variety of anilines and 2-hydroxybenzaldehydes under Lewis acid catalysis to yield the title compounds in 4-24 hours of reaction time, in moderate to high yields and excellent diastereoselectivity. Of the Lewis acid catalysts deployed [Sc(OTf)3, Al(OTf)3, Cu(OTf)2, CuOTf, I2, InCl3, and La(OTf)3] in various solvents (acetonitrile, THF, dichloromethane, 1,2-dichloroethane and diethyl ether) at room and elevated temperatures, Sc(OTf)3 (10 mol%) in acetonitrile at 70 °C gave the best results, with excellent diastereoselectivity. CAN-mediated oxidative ring opening of the pentacyclic N-heterocycle gave the corresponding enantiometrically pure chromenoquinoline bearing a pendant sugar moiety.

Chemical profiling, bio-guided purification, and cytotoxic effect of two African spices: Hypodaphnis zenkeri Engl. Stapf (Lauraceae) and Staudtia kamerunensis warb (Myristicaceae) on human prostate cancer cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: Prostate cancer remains a significant burden in low- and middle-income countries and the second leading cause of death around the world. Spices used in daily cuisine contain interesting phytochemical components capable of helping prevent and cure cancer. AIM: This study aims to give sufficient phytochemical information on two understudied species, Staudtia kamerunensis Warb. (Myristicaceae) and Hypodaphnis zenkeri Engl. Stapf. (Lauraceae), and to study their cytotoxicity against prostate cancer cells in its early form and when they have developed metastasis. MATERIALS AND METHODS: To reach this goal, normal procedures for phytochemical analysis were followed; these include collection, drying, crushing and extraction of plant materials using organic solvents. GC-MS (Gas chromatography- Mass Spectrometry) was used to evaluate the volatile phytochemicals contained in the extracts, and open-column chromatography was used to isolate the pure compounds used in this study. A bio-guided exploration of Hypodaphnis zenkeri (Lauraceae) (leaves, seeds, stems) guided us in selecting the extract for further analysis. An established MTT assay was used to measure cell proliferation. Three prostate cancer cell lines were considered in this study, DU145 and PC3, human androgens-independent prostate carcinoma cells and LNCaP, which are cells derived from metastasis of a human prostate and respond to androgens, oestrogens and progestins. The eight compounds isolated were characterized using HREIMS, 1D and 2D NMR. RESULTS: Among the three extracts from Hypodaphnis zenkeri, considered for biological testing, the leaf extract displayed better activities with a CC50 of 180 µg/mL against DU 145 cells, 184 µg/mL against PC3 cells and 194 µg/mL against LNCaP cells. These results were justified when GC-MS analysis of the different extracts was performed. Fifty compounds were identified from the leaves, representing 96.06% of the volatile components, with most displaying anticancer activities or activities against vectors favorizing cancer growth (inflammation, etc.). An attempt to isolate the active principle responsible for the cancer activity led to the isolation of five pure compounds, namely Eicosane [1], Nonacos-1-ene [2], Palmitic acid [3], Glucoside Stigmasterol [4] and Butane-1,2,3,4-tetraol [5]. Eicosane was identified as being responsible in part for the observed activity, even though it exhibited weak cytotoxicity with the lowest CC50 equal to 30 µg/mL against DU 145 cells. Staudtia kamerunensis sap was investigated in our previous studies with the isolation of Oleanan-12-ene-2α,3ß -diol [6] and 2α, 3ß -dihydroxylup-20-ene [7] among the major components, with significant antibacterial properties. Oleanan-12-ene-2α,3ß -diol [7] in this study displayed a CC50 of 20 µg/mL against DU145 cells, 22 µg/mL against PC3 cells, 18 µg/mL against LNCaP cells, and 32 µg/mL in HMEC affording a selectivity index >2. Contrary to what was observed in our previous study, the activity of Oleanan-12-ene-2α,3ß -diol was lost in the presence of 2α, 3ß -dihydroxylup-20-ene. CONCLUSION: the cytotoxic effect of extract from Staudtia and Hypodaphnis genera and pure isolates are here reported for the first time, as well as the pure isolates. These studies exhibit the cytotoxic potential of two traditional African spices and, more specifically, Oleanan-12-ene-2α,3ß -diol and eicosane, isolated from these plant species.

From wandering weeds to pharmacy: An insight into traditional uses, phytochemicals and pharmacology of genus Chromolaena (Asteraceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Chromolaena species, of the Asteraceae family, are distributed across the tropical and the temperate regions of Africa, the Americas, southern Asia, and Australia. Despite "falling out of favour" among the people because of their "weedy" nature, Chromolaena species have indisputable long medicinal history in the treatment of malaria, nasal congestion, inflammation, eye disorders, asthma, cough, flu, headache, and cold. AIM OF THE REVIEW: The aim of this review is to systematically summarize the current knowledge on ethnopharmacology, phytochemistry, pharmacology, toxicology, and real-time scientific applications of the genus Chromolaena after its re-classification from genus Eupatorium, as well as to proffer integrated approaches in maximizing their therapeutic values despite their "weedy" nature. MATERIALS AND METHODS: First, the current species in the genus were verified by "The Plant List" (http://www.theplantlist.org) and "Royal Botanic Gardens, Kew/Missouri Botanical Garden" (http://mpns.kew.org/mpns-portal/). Second, the relevant information on each of the identified species was gathered from following databases: Google Scholar, Online Wiley library, ScienceDirect, SciFinder, Scopus, PubMed. Scientific literature was searched from inception till August 2021. RESULTS: More than 190 phytochemicals have been isolated and identified from 27 species of the genus, including flavonoids, alkaloids, triterpenoids, diterpenoids, sesquiterpenoids, steroids, fatty acids, and coumarins among others. Pharmacological investigations, both in vitro and in vivo, have shown that the extracts and the compounds have antimicrobial, anticancer, antioxidant, insecticidal, anti-inflammatory, and anti-diabetic activities among others. CONCLUSIONS: Many species of genus have potential therapeutic values, and hence they are more than "wandering" weeds. In addition, there is growing interest in the real-time scientific applications of the genus in the production of pharmacological polyherbal products, and this should serve as a stimulus to strategically develop integrated control approaches for preserving these species, with a view of maximizing their therapeutic values and reducing their cost of eradication.

In vitro anti-plasmodial activity of Dicoma anomala subsp. gerrardii (Asteraceae): identification of its main active constituent, structure-activity relationship studies and gene expression profiling.

BACKGROUND: Anti-malarial drug resistance threatens to undermine efforts to eliminate this deadly disease. The resulting omnipresent requirement for drugs with novel modes of action prompted a national consortium initiative to discover new anti-plasmodial agents from South African medicinal plants. One of the plants selected for investigation was Dicoma anomala subsp. gerrardii, based on its ethnomedicinal profile. METHODS: Standard phytochemical analysis techniques, including solvent-solvent extraction, thin-layer- and column chromatography, were used to isolate the main active constituent of Dicoma anomala subsp. gerrardii. The crystallized pure compound was identified using nuclear magnetic resonance spectroscopy, mass spectrometry and X-ray crystallography. The compound was tested in vitro on Plasmodium falciparum cultures using the parasite lactate dehydrogenase (pLDH) assay and was found to have anti-malarial activity. To determine the functional groups responsible for the activity, a small collection of synthetic analogues was generated - the aim being to vary features proposed as likely to be related to the anti-malarial activity and to quantify the effect of the modifications in vitro using the pLDH assay. The effects of the pure compound on the P. falciparum transcriptome were subsequently investigated by treating ring-stage parasites (alongside untreated controls), followed by oligonucleotide microarray- and data analysis. RESULTS: The main active constituent was identified as dehydrobrachylaenolide, a eudesmanolide-type sesquiterpene lactone. The compound demonstrated an in vitro IC50 of 1.865 µM against a chloroquine-sensitive strain (D10) of P. falciparum. Synthetic analogues of the compound confirmed an absolute requirement that the α-methylene lactone be present in the eudesmanolide before significant anti-malarial activity was observed. This feature is absent in the artemisinins and suggests a different mode of action. Microarray data analysis identified 572 unique genes that were differentially expressed as a result of the treatment and gene ontology analysis identified various biological processes and molecular functions that were significantly affected. Comparison of the dehydrobrachylaenolide treatment transcriptional dataset with a published artesunate (also a sesquiterpene lactone) dataset revealed little overlap. These results strengthen the notion that the isolated compound and the artemisinins have differentiated modes of action. CONCLUSIONS: The novel mode of action of dehydrobrachylaenolide, detected during these studies, will play an ongoing role in advancing anti-plasmodial drug discovery efforts.

CAN-mediated oxidations for the synthesis of xanthones and related products.

Reaction of (2,4,5-trimethoxyphenyl)(2-hydroxyphenyl)methanone with ceric ammonium nitrate furnished the xanthone, 2,3-dimethoxy-9H-xanthen-9-one. Under the same conditions the related (1,4-dimethoxynaphthalen-2-yl)(2-hydroxyphenyl)methanone resulted in the formation of 12a-methoxy-5H-benzo[c]xanthenes 5,7(12aH)-dione. Other examples of this novel transformation are also outlined.

Bidirectional racemic synthesis of the biologically active quinone cardinalin 3.

Readily available 2,2',6,6'-tetramethoxy-1,1'-biphenyl was transformed in 14 synthetic steps into the natural product cardinalin 3 using a bidirectional approach. One of the key steps was the formation of the cis-1,3-dimethylnaphtho[2,3-c]pyran ring. (+/-)-1,1'-[6,6'-Diallyl-5,5'-bis(benzyloxy)-1,1',3,3'-tetramethoxy-2,2'-binaphthalene-7,7'-diyl]diethanol was treated with O(2) in the presence of CuCl(2) and catalytic PdCl(2) to afford 5,5'-bis(benzyloxy)-7,7',9,9'-tetramethoxy-1,1',3,3'-tetramethyl-1H,1'H-8,8'-bibenzo[g]isochromene. Hydrogenation of this compound afforded 7,7',9,9'-tetramethoxy-cis-1,3-cis-1',3'-tetramethyl-3,3',4,4'-tetrahydro-1H,1'H-8,8'-bibenzo[g]isochromene-5,5'-diol in quantitative yield, which was converted in 3 steps to cardinalin 3.

1,3-dipolar cycloaddition chemistry for the preparation of novel indolizinone-based compounds.

[Chemical reaction: See text] Starting from methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydroindolizine-8-carboxylate, obtained by a Rh(II)-catalyzed 1,3-dipolar cycloaddition reaction of 1-(2-benzenesulfonyl-2-diazoacetyl)pyrrolidin-2-one and methyl acrylate, several indolo- and furano-fused indolizinones were efficiently prepared. In the first case, a palladium-mediated C-N coupling of the triflate with a variety of substituted anilines provided the desired methyl 5-oxo-6-(arylamino)-1,2,3,5-tetrahydroindolizine-8-carboxylates in high yield. Methyl 6-(2-bromophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate as well as its decarboxylated analogue, 6-(2-bromophenylamino)-2,3-dihydro-1H-indolizin-5-one, were synthesized in excellent yield and were found to undergo an intramolecular Heck cyclization to give 1,2,3,6-tetrahydroindolizino[6,7-b]indol-5-ones. To prepare furano-fused indolizinones, methyl 6-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate was etherified with different allyl halides, and the resultant allyl ethers were subjected to a thermal Claisen rearrangement to give the corresponding methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,4-tetrahydroindolizine-8-carboxylates. Cyclization under Wacker oxidation conditions afforded methyl 2-methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-s-indacene-4-carboxylates in near-quantitative yield.

The synthesis of ventiloquinone L, the monomer of cardinalin 3.

Readily available ethyl-4-acetoxy-6,8-dimethoxynaphthalene-2-carboxylate was converted into 1-[3-allyl-4-(benzyloxy)-6,8-dimethoxy-2-naphthyl)-1-ethanol in seven steps. Subjection of this compound to Wacker oxidation conditions provided 5-benzyloxy-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochromene in good yield. Hydrogenation of the isochromene afforded (+/-)-cis-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochroman-5-ol as the major product, which was readily converted into ventiloquinone L.