Synthesis, In Silico Study, Antibacterial and Antifungal Activities of N-phenylbenzamides.

Antibiotic and antifungal resistance problems have been prevalent in recent decades. One of the efforts to solve the problems is to develop new medicines with more potent antibacterial and antifungal activity. N-phenylbenzamides have the potential to be developed as antibacterial and antifungal medicine. This study aimed to synthesize N-phenylbenzamides and evaluate their in silico and in vitro antibacterial and antifungal activities. The in silico studies conducted absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions along with molecular docking studies. ADMET predictions used pkCSM software online, while the docking studies used MVD software (Molegro ® Virtual Docker version 5.5) on Aminoglycosid-2 ″-phosphotransferase-IIa (APH2 ″-IIa) enzyme with protein data bank (PDB) ID code 3HAV as antibacterial and aspartic proteinases enzyme (Saps) with PDB ID code 2QZX as an antifungal. In vitro, antibacterial and antifungal tests were carried out using the zone of inhibition (ZOI) method. The five N-phenylbenzamides (3a-e) were successfully synthesized with a high yield. Based on in silico and in vitro studies, compounds 3a-e have antibacterial and antifungal activities, where they can inhibit the growth of Gram-positive bacteria (Staphylococcus aureus), Gram-negative (Escherichia coli), and Candida albicans. Therefore, compounds 3a-e can be developed as a topical antibacterial and antifungal agent.

New ψ-Santonin Derivatives from Crossostephium chinense and Their Anti-Proliferative Activities against Leishmania major and Human Cancer Cells A549.

Previously, we reported two cytotoxic ψ-santonin-amino acid conjugates isolated from the EtOAc layer of Crossostephium chinense. However, a further phytochemical investigation seems to be required because of the few reports of similar derivatives. In this study, we targeted the 1-BuOH layer, which resulted in the isolation of seven new ψ-santonin derivatives (1-7) together with ten known compounds (8-17). The structures of 1-7 were elucidated based on spectroscopic methods, including 1D and 2D NMR experiments (1H, 13C, DEPT, COSY, HSQC, and HMBC), IR spectrum, and high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS). The stereochemistry of new compounds was confirmed by NOESY and ECD calculations. All isolated compounds were evaluated by in vitro experiments for their anti-proliferative activities against Leishmania major, human lung cancer cell line A549, and Vero cells. As a result, most of the ψ-santonin derivatives, especially 1-5, showed significant cytotoxicity against L. major with a lower IC50 than the positive control we used (miltefosine).

Two New Cytotoxic Sesquiterpene-Amino Acid Conjugates and a Coumarin-Glucoside from Crossostephium chinense.

The Asteraceae family is a promising source of bioactive compounds, such as the famous Asteraceae plants Tanacetum cinerariifolium (pyrethrin) and Artemisia annua (artemisinin). As a result of our series of phytochemical studies of the subtropical plants, two novel sesquiterpenes, named crossoseamines A and B in this study (1 and 2, respectively), one undescribed coumarin-glucoside (3), and eighteen known compounds (4-21) were isolated from the aerial part of Crossostephium chinense (Asteraceae). The structures of isolated compounds were elucidated by spectroscopic methods, including 1D and 2D NMR experiments (1H, 13C, DEPT, COSY, HSQC, HMBC, and NOESY), IR spectrum, circular dichroism spectrum (CD), and high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS). All isolated compounds were evaluated for their cytotoxic activities against Leishmania major, Plasmodium falciparum, Trypanosoma brucei (gambiense and rhodesiense), and human lung cancer cell line A549 because of the high demand for the discovery of new drug leads to overcome the present side effects and emerging drug-resistant strains. As a result, the new compounds (1 and 2) showed significant activities against A549 (IC50, 1: 3.3 ± 0.3; 2: 12.3 ± 1.0 µg/mL), L. major (IC50, 1: 6.9 ± 0.6; 2: 24.9 ± 2.2 µg/mL), and P. falciparum (IC50, 1: 12.1 ± 1.1; 2: 15.6 ± 1.2 µg/mL).

Crotofolane-Type Diterpenoids: Crotocascarins R-V, Rearranged Trinorcrotofolane: Crotocascarin δ and a Phorbol Derivative from the Leaves of Croton cascarilloides.

Five new crotofolanes, named crotocascarins R-V (1-5), one rearranged trinorcrotofolane, crotocascarin δ, and one phorbol derivative were isolated from the EtOAc-soluble fraction of the MeOH extract of the leaves of Croton cascarilloides. Crotocascarins R (1), T (3), and U (4) possessed isobutyric acid as an acyl moiety and crotocascarin B (2) an acetyl group, whereas crotocascarin V (5) was elucidated to be a hydroxylated compound of crotocascarin K at the 9-position. Crotocascarin δ (6) was a trinor rearranged crotofolane with a tertiary hemiketal functional group at the 8-position. The absolute configuration of the 8-position was determined by the comparison of the experimental electronic circular dichroism (ECD) spectrum and calculated ECD spectra. Compound 7 was a phorbol ester derivative with a peroxide functional group. The fatty acid attached at the 12-position was found to be a single species-i.e., lauric acid (C-12)-from the evidence of the mass spectral data.

Omphalines A-E: ent-Rosane-Type Diterpenoids from the Madagascar Endemic Plant, Omphalea oppositifolia.

From the less polar fraction of the MeOH extract of the leaves and twigs of Omphalea oppositifolia, five new ent-rosane-type diterpenoids, named omphalines A-E (1-5), were isolated together with one known compound, 7-keto-ent-kaurane-16ß,17-diol (6), by a combination of various kinds of chromatography. The structure of omphaline A (1) was elucidated to be 19-nor-ent-rosane-4,15-diene-2ß,6α-diol-3-one. Omphalines B (2), C (3), D (4), and E (5) possessed two double bonds at 5- and 15-positions, and hydroxy functional groups at 3ß-, 2α,3α-, 2α,3ß-, and 2α,19-positions, respectively. The absolute configuration of 1 was determined by the comparison of the experimental electronic circular dichroism (ECD) spectrum and calculated ECD spectra.

Diterpenes and sterols from the Red Sea soft coral Sarcophyton trocheliophorum and their cytotoxicity and anti-leishmanial activities.

The ethyl acetate and dichloromethane-soluble fractions, from a soft coral Sarcophyton trocheliophorum total methanolic extract, exhibited significant anti-leishmanial and cytotoxic activities. These active fractions yielded a new cembranoid diterpene (1), two known analogues [sarcotrocheliol (2) and sarcophine (3)], and two sterols [(24S)-24-methylcholesterol (4) and gorgosterol (5)]. The structure of the new diterpene (1) was determined via a detailed analysis of its spectroscopic data. Compounds 3 and 5 demonstrated noticeable cytotoxicity on A549 (IC50 17.4 ± 1.9 µg/ml) and HepG2 (IC50 17.7 ± 1.5 µg/ml) cell lines, respectively. None of the isolates 1‒5 showed detectable anti-leishmanial activity (IC50 >100 µg/ml).

Ameliorative Effect of Ocimum forskolei Benth on Diabetic, Apoptotic, and Adipogenic Biomarkers of Diabetic Rats and 3T3-L1 Fibroblasts Assisted by In Silico Approach.

Diabetes mellitus (DM) is a complicated condition that is accompanied by a plethora of metabolic symptoms, including disturbed serum glucose and lipid profiles. Several herbs are reputed as traditional medicine to improve DM. The current study was designed to explore the chemical composition and possible ameliorative effects of Ocimum forskolei on blood glucose and lipid profile in high-fat diet/streptozotocin-induced diabetic rats and in 3T3-L1 cell lines as a first report of its bioactivity. Histopathological study of pancreatic and adipose tissues was performed in control and treatment groups, along with quantification of glucose and lipid profiles and the assessment of NF-κB, cleaved caspase-3, BAX, and BCL2 markers in rat pancreatic tissue. Glucose uptake, adipogenic markers, DGAT1, CEBP/α, and PPARγ levels were evaluated in the 3T3-L1 cell line. Hesperidin was isolated from total methanol extract (TME). TME and hesperidin significantly controlled the glucose and lipid profile in DM rats. Glibenclamide was used as a positive control. Histopathological assessment showed that TME and hesperidin averted necrosis and infiltration in pancreatic tissues, and led to a substantial improvement in the cellular structure of adipose tissue. TME and hesperidin distinctly diminished the mRNA and protein expression of NF-κB, cleaved caspase-3, and BAX, and increased BCL2 expression (reflecting its protective and antiapoptotic actions). Interestingly, TME and hesperidin reduced glucose uptake and oxidative lipid accumulation in the 3T3-L1 cell line. TME and hesperidin reduced DGAT1, CEBP/α, and PPARγ mRNA and protein expression in 3T3-L1 cells. Moreover, docking studies supported the results via deep interaction of hesperidin with the tested biomarkers. Taken together, the current study demonstrates Ocimum forskolei and hesperidin as possible candidates for treating diabetes mellitus.

Isolation of Three New Diterpenes from Dodonaea viscosa.

An investigation into the methanol extracts obtained from the stems of Dodonaea viscosa led to the isolation of one nor-clerodane diterpene (1) and two labdane diterpenes (2, 3), as well as 17 known compounds (4-20). The structures of these compounds were elucidated based on chemical and spectral evidence. The stereochemical structure of the nor-clerodane diterpene was confirmed via its circular dichroism spectrum and calculated electronic circular dichroism spectrum. Isolated compounds were evaluated for their inhibitory effects on collagenase and tyrosinase. Since 5,7,4'-trihydroxy-3'-(4-hydroxy-3-methylbutyl)-5'-(3-methylbut-2-enyl)-3,6-dimethoxyflavone (9) showed collagenase inhibitory activity and scopoletin (12) had significant tyrosinase inhibitory activity, they were considered to be good candidates for cosmetic agents.

Six New Phenylpropanoid Derivatives from Chemically Converted Extract of Alpinia galanga (L.) and Their Antiparasitic Activities.

Chemical conversion of the extract of natural resources is a very attractive way to expand the chemical space to discover bioactive compounds. In order to search for new medicines to treat parasitic diseases that cause high morbidity and mortality in affected countries in the world, the ethyl acetate extract from the rhizome of Alpinia galanga (L.) has been chemically converted by epoxidation using dioxirane generated in situ. The biological activity of chemically converted extract (CCE) of A. galanga (L.) significantly increased the activity against Leishmania major up to 82.6 ± 6.2 % at 25 µg/mL (whereas 2.7 ± 0.8% for the original extract). By bioassay-guided fractionation, new phenylpropanoids (1-6) and four known compounds, hydroquinone (7), 4-hydroxy(4-hydroxyphenyl)methoxy)benzaldehyde (8), isocoumarin cis 4-hydroxymelein (9), and (2S,3S,6R,7R,9S,10S)-humulene triepoxide (10) were isolated from CCE. The structures of isolated compounds were determined by spectroscopic analyses of 1D and 2D NMR, IR, and MS spectra. The most active compound was hydroquinone (7) with IC50 = 0.37 ± 1.37 µg/mL as a substantial active principle of CCE. In addition, the new phenylpropanoid 2 (IC50 = 27.8 ± 0.34 µg/mL) also showed significant activity against L. major compared to the positive control miltefosine (IC50 = 7.47 ± 0.3 µg/mL). The activities of the isolated compounds were also evaluated against Plasmodium falciparum, Trypanosoma brucei gambisense and Trypanosoma brucei rhodeisense. Interestingly, compound 2 was selectively active against trypanosomes with potent activity. To the best of our knowledge, this is the first report on the bioactive "unnatural" natural products from the crude extract of A. galanga (L.) by chemical conversion and on its activities against causal pathogens of leishmaniasis, trypanosomiasis, and malaria.

Symplocosins C-P: Fourteen Triterpene Saponins from the Leaves of Symplocos cochinchinensis var. philippinensis.

Extensive phytochemical work on the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Symplocos cochinchinensis var. philippinensis resulted in the isolation of 14 new triterpenene saponins, along with four known ones. Their structures were elucidated by comparison of NMR spectroscopic data with related compounds reported in the literature. Three oleanane-type saponins, symplocosins K, M, and P, possessed glucuronic acid as a sugar component, and their carboxyl groups appeared as methyl esters. These are probably formed during extraction and isolation procedures. Symplocosin K (9) showed moderate cytotoxicity toward A549 cells. In addition, all isolated compounds did not show α-glucosidase inhibitory activity.

Zanthosides A-D: Four Aromatic Glucosides from the Leaves of Zanthoxylum ailanthoides.

From the leaves of Zanthoxylum ailanthoides, four new phenolic glucosides, termed zanthosides A-D (1-4), were isolated. Their structures were elucidated by means of spectroscopic evidence. Zanthoside A was enzymatically hydrolyzed and thus the aglycone obtained was found to be (1'S,2'R)-(-)-trans-decursidinol, isolated from Angelica decursiva.

New Methyl Threonolactones and Pyroglutamates of Spilanthes acmella (L.) L. and Their Bone Formation Activities.

In our continuing research for bioactive constituents from natural resources, a new methyl threonolactone glucopyranoside (1), a new methyl threonolactone fructofuranoside (2), 2 new pyroglutamates (3 and 4), and 10 known compounds (5-14) were isolated from the whole plant of Spilanthes acmella (L.) L. The structures of these compounds were determined based on various spectroscopic and chemical analyses. All of the isolated compounds were evaluated on bone formation parameters, such as ALP (alkaline phosphatase) and mineralization stimulatory activities of MC3T3-E1 cell lines. The results showed that the new compound, 1,3-butanediol 3-pyroglutamate (4), 2-deoxy-D-ribono-1,4-lactone (6), methyl pyroglutamate (7), ampelopsisionoside (10), icariside B1 (11), and benzyl α-L-arabinopyranosyl-(1→6)-ß-D-glucopyranoside (12) stimulated both ALP and mineralization activities.

Lasianosides F-I: A New Iridoid and Three New Bis-Iridoid Glycosides from the Leaves of Lasianthus verticillatus (Lour.) Merr.

A series of iridoid glycosides were isolated from the leaves of Lasianthus verticillatus (Lour.) Merr., belonging to family Rubiaceae. A new iridoid glycoside, lasianoside F (1), and three new bis-iridoid glycosides, lasianosides G-I (2-4), together with four known compounds (5-8) were isolated. The structures were established by spectroscopic methods, including 1D and 2D NMR experiments (1H, 13C, DEPT, COSY, HSQC, HMBC, and NOESY) in combination with HR-ESI-MS and CD spectra.

Isolation of Sesquiterpene-Amino Acid Conjugates, Onopornoids A-D, and a Flavonoid Glucoside from Onopordum alexandrinum.

Previous phytochemical investigations have revealed the presence of a variety of compounds such as pyrrolidine derivatives, flavonoids, and megastigmanes in Egyptian plants. Onopordum alexandrinum has been traditionally used by the natives for treatment of skin cancers and leprosy. In this paper the isolation of four new sesquiterpene-amino acid conjugates, onopornoids A-D (1-4), i.e., three elemanes and one germacrane, and a new acylated flavonoid glucoside (5) along with nine known compounds (6-14) from the whole aerial parts of the title plant is discussed. The structures were elucidated based on chemical and spectroscopic/spectrometric data.

Ebenamariosides A-D: Triterpene Glucosides and Megastigmanes from the Leaves of Diospyros maritima.

The 1-BuOH-soluble fraction of the methanol (MeOH) extract of Diospyros maritima was separated by chromatographic techniques to give three new oleanane-type and one new ursane-type triterpene glucoside, named ebenamariosides A-D (1-4); two megastigmanes were also isolated. The structures of triterpene glucosides was elucidated with extensive investigation by one and two dimensional NMR spectroscopy and the structures were confirmed by partial enzymatic hydrolyses to give the corresponding mono-glucosides and aglycones. The structures of the megastigmanes, including their absolute stereochemistries, were elucidated by spectroscopic evidence and by the modified Mosher's method. Two megastigmanes were chemically correlated and their absolute structures were unambiguously determined. The cytotoxicity of the triterpene glucosides and their degradation products were assayed. They did not show any significant activity.

Four New Flavonoids Isolated from the Aerial Parts of Cadaba rotundifolia Forssk. (Qadab).

Cadaba rotundifolia (Forssk.) (family: Capparaceae; common name: Qadab) is one of four species that grow in the Red Sea costal region in the Kingdom of Saudi Arabia. The roots and leaves of C. rotundifolia is traditionally used to treat tumors and abscesses in Sudan. A previous phytochemical study of the roots yielded a quaternary alkaloid, but no report on chemical constituents of the aerial parts of the C. rotundifolia growing in Saudi Arabia has been issued so far. Oxidative stress and advanced glycation end products (AGEs) are thought as causal factors in many degenerative diseases, such as Alzheimer's disease, diabetes, atherosclerosis and aging. In this study, a total of twenty compounds, including four previously undescribed acylated kaempferol glucosides, were isolated from the aerial parts of C. rotundifolia collected in Saudi Arabia. These new compounds were identified as kaempferol 3-O-[2-O-(trans-feruloyl)-3-O-ß-d-glucopyranosyl]-ß-d-glucopyranoside (1), kaempferol 3-O-ß-neohesperidoside-7-O-[2-O-(cis-p-coumaroyl)-3-O-ß-d-glucopyranosyl]-ß-d-glucopyranoside (2), kaempferol 3-O-[2,6-di-O-α-l-rhamnopyranosyl]-ß-d-glucopyranoside-7-O-[6-O-(trans-feruloyl)]-ß-d-glucopyranoside (3) and kaempferol 3-O-[2,6-di-O-α-l-rhamnopyranosyl]-ß-d-glucopyranoside-7-O-[6-O-(trans-p-coumaroyl)]-ß-d-glucopyranoside (4). Their structures were established based on UV-visible, 1D, 2D NMR, and HR-ESI-MS analyses. Of the assayed compounds, 17 and 18 showed potent radical scavenging activity with IC50 values of 14.5 and 11.7 µM, respectively, and inhibitory activity toward AGEs together with compound 7 with IC50 values 96.5, 34.9 and 85.5 µM, respectively.

Lasianosides A-E: New Iridoid Glucosides from the Leaves of Lasianthus verticillatus (Lour.) Merr. and Their Antioxidant Activity.

The genus Lasianthus (Rubiaceae) consists of approximately 180 species, of which the greatest species diversity is found in tropical Asia. Some of the Lasianthus species have been used in folk medicine to treat tinnitus, arthritis, fever, and bleeding. Lasianthus verticillatus (Lour.) Merr. (Syn. Lasianthus trichophlebus auct. non Hemsl.) is a shrub, branchlets terete about 1.5-3 m in height. This paper studies the chemical composition of the leaves of L. verticillatus for the first time, which resulted in the isolation of five undescribed iridoid glucosides, lasianosides A-E (1-5), together with three known compounds (6-8). The undescribed structures of isolated compounds (1-5) were characterized by physical and spectroscopic data analyses, including one-dimensional (1D) and two-dimensional (2D) NMR, IR, UV, and high-resolution electrospray ionization mass spectra (HR-ESI-MS). Furthermore, the electronic circular dichroism data determined the absolute configurations of the new compounds. The free radical scavenging properties of isolated compounds was assessed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and their cytotoxicity was assessed toward human lung cancer cell line A549 by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Among the isolated compounds, 3 and 4 displayed potent radical scavenging activities with IC50 values of 30.2 ± 1.8 and 32.0 ± 1.2 µM, which were comparable to that of Trolox (29.2 ± 0.39 µM), respectively, while 5 possessed moderate activity with an IC50 value of 46.4 ± 2.3 µM. None of the isolated compounds exerted cytotoxicity against human cell line A549. As a result, lasianosides C, D, and E have the potential to be non-toxic safe antioxidant agents.

Okinawan Subtropical Plants as a Promising Resource for Novel Chemical Treasury.

The Okinawa Islands are a crescent-shaped archipelago and their natural forests hold a huge variety of unique subtropical plants with relatively high endemism. We have performed phytochemical study on Okinawan subtropical plants for many years. In this review, we describe our recent research progress on the isolation of new compounds and their various bioactivities.

Alkylated Benzoquinones: Quinquequinones A­H from the Leaves of Ardisia quinquegona and Their Anti-Leishmania Activity [corrected].

Eight alkylated benzoquinone derivatives, named ardisiaquinones A-H, were isolated together with four known compounds from the leaves of Ardisia quinquegona using a combination of different chromatography techniques. Their structures were elucidated by spectroscopy and by the preparation of methyl ethers. Anti-Leishmania activity and cytotoxicity of the isolated compounds were assayed. Some compounds showed moderate anti-Leishmania activity, however, always associated with cytotoxicity.

Eight ent-Kaurane Diterpenoid Glycosides Named Diosmariosides A-H from the Leaves of Diospyros maritima and Their Cytotoxic Activity.

From the leaves of Diospyros maritima, collected from Okinawa Island, eight new glycosides based on ent-kaurane-type diterpenoids, entitled diosmariosides A-H, were isolated. The absolute structure of diosmarioside E (5) was determined by X-ray crystallographic analysis. The structure of diosmarioside H was elucidated to be a dimeric compound between diosmarioside A and a sugeroside through a ketal bond. An assay of cytotoxicity towards the lung adenocarcinoma (A549) cell line was performed. Among the compounds isolated, only diosmarioside D (4) and sugeroside 9 showed strong activity. The anti-microbial activity toward multi-drug resistant strains was also determined, but no activity was observed.