Synthesis and anti-tumor activity of glycosyl oxadiazoles derivatives

A new series of glycosyl oxadiazoles compounds were synthesized and characterized through ¹H NMR, ¹³C NMR, IR and HRMS. The anti-tumor activities for MDA-MB-231 of all these new compounds were screened in vitro by MTT assay. Due to the modification of gastrodin analogues, the anti-tumor activities of these 1,3,4-oxadiazoles derivatives were greatly improved. Six compounds (6c, 6d, 6i, 6j, 6k and 6l) displayed relatively higher MDA-MB-231 potency with IC₅₀ values (0.89, 0.26, 1.35, 3.60, 0.95 and 1.08 μM) compared with the reference medicine Rosiglitazone (5.23 μM).     

Synthesis and antiprotozoal activity of nitazoxanide–N-methylbenzimidazole hybrids

A series of a novel hybrid compounds between nitazoxanide and N-methylbenzimidazole were synthesized starting from the corresponding N-methyl-2-nitroanilines. The new hybrid compounds (1–13) were evaluated in vitro against Giardia intestinalis, Entamoeba histolytica, Trichomonas vaginalis. NTZ, MTZ and ABZ were used as drug standards. Experimental evaluations revealed all of the new compounds (1–13) were active and showed strong activity against the three protozoa, particularly with E. histolytica where the IC₅₀ values ranged between 3 and 69 nM.Overall, compounds 2, 5, 7, 8, 9, 11 and 12 stood out with values lower than 87 nM for all three protozoa, comparatively better than the reference drugs.     

Phytochemistry and antiglycation activity of Aloe sinkatana Reynolds

A new anthraquinone along with 10 known compounds were isolated from the leaves of Aloe sinkatana Reynolds (Aloaceae), and their structures were elucidated as the new compound 2,8-dihydroxy-6-(hydroxymethyl)-1-methoxyanthracene-9,10-dione (1) and the known compounds Aloe-emodin (2), feralolide (3), 1-hydroxy-5-methoxy-3-methyl-9,10 dihydroanthracene 9,10-dione (4), β-sitosterol (5), β-sitosterol with glycosidic bond (6), microdontin (7), homoaloins A (8) and B (9) and aloins A (10) and B (11). Characterization of compounds 1–9 was based on spectral analyses and comparison with reported data, particularly the new compound 1 was identified by 1D- and 2D NMR, mass spectroscopic and X-ray crystallography analyses. Antiglycation activity of the extracts and isolated compounds were carried out using the hemoglobin-δ-gluconolactone and glucose–bovine serum albumin assays. The results obtained showed that MeOH and EtOAc extracts as well as compound 1 showed an inhibitory effect on early stage protein glycation. Compound 1 also showed significant inhibitory effects against glucose-induced advanced glycation end-products.     

Synthesis and cytotoxic activity of gamma-aryl substituted alpha-alkylidene-gamma-lactones and alpha-alkylidene-gamma-lactams

A series of 5-aryl-3-alkylidenedihydrofuran-2(3H)-ones 6a–g″ and 11a,b as well as 5-aryl-3-methylidenepyrrolidin-2-ones 10a–c and 12 were synthesized starting from 4-aryl-2-diethoxyphosphoryl-4-oxobutanoates 3a–g. Reaction sequence includes reduction or reductive amination of the carbonyl group, lactonization or lactamization step and finally the Horner–Wadsworth–Emmons olefination of aldehydes using thus obtained 5-aryl-3-diethoxyphosphoryl-3,4-dihydrofuran-2(5H)-ones 5a–g″ or 5-aryl-3-diethoxyphosphorylpyrrolidin-2-ones 9a–c. Furanones 6 and 11, as well as pyrrolidinones 10 and 12, were evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines HL-60 and NALM-6. Several of the obtained furanones proved to be very potent against all three cell lines with IC₅₀ values lower than 6 μM. Structure–activity relationships of these compounds, as well as 5-alkyl or 5-arylmethyl-3-methylidenedihydrofuran-2(3H)-ones 13a–e, previously obtained in our laboratory, are discussed.     

In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin

Isoliquiritigenin (ISL), a chalcone and liquiritigenin (LTG), a flavonoid found in licorice roots and several other plants. ISL displays antioxidant, anti-inflammatory, antitumor and hepatoprotective activities whereas LTG is an estrogenic compound, acts as an agonist selective for the β-subtype of the oestrogen receptor. Both the phenolics were isolated from the rhizomes of Glycyrrhiza glabra. Five derivatives from ISL and four derivatives from LTG were synthesized. All the compounds were established by extensive spectroscopic analyses and screened through oral glucose tolerance test to gain preliminary information regarding the antihyperglycemic effect in normal Swiss albino male mice. ISL (1), ISL derivatives 3, 4, 5, 7 and LTG derivatives 9 and 10 showed significant blood glucose lowering effect. The structure–activity relationship indicated that the presence of ether and ester groups in ISL and LTG analogues are important for exhibiting the activity. Compounds 1, 4 and 10 were selected for in vivo antidiabetic activity and found to be potential candidates for treatment of diabetes. It is the first report on antidiabetic activity of ISL derivative 4 and LTG derivative 10.     

Synthesis and the hepatoprotective activity of dibenzocyclooctadiene lignan derivatives

The halogenated and oxidized derivatives (1a–1e, 1a′–1c′, 2a–2d, 2a′–2b′, 3a–3e, 3′ and 3a′–3b′) of schizandrin (1), schizandrin B (2) and schisanhenol (3) were synthesized. The hepatoprotective effects of these dibenzocyclooctadiene lignan analogues against CCl₄-induced injury were preliminarily evaluated. Most of the analogues exhibited higher protective effects than the positive control biphenyldicarboxylate (DDB). Among these active analogues, dichloroschisanhenol (3a) exhibited the strongest protective activity (cell survival rate exceeding 98.0%).     

Synthesis and cytokinin activity of N-acylaminodeazapurines

Three 7-acylaminoimidazo[4,5-b]pyridines, namely 7-pentanoylaminoimidazo[4,5-b]pyridine (1), 7-benzoylaminoimidazo[4,5-b]pyridine(2), and 7-(2-furoylamino)imidazo[4,5-b]pyridine(3), six 4-acylaminoimidazo[4,5-c]pyridines, namely 4-propionylaminoimidazo[4,5-c]pyridine(4), 4-butyryl-aminoimidazo[4,5-c]pyridine(5), 4-pentanoylaminoimidazo[4,5-c]pyridine(6) 4-hexanoylaminoimidazo[4,5-c]pyridine(7),4-benzoylaminoimidazo[4,5-c]pyridine(8), and 4-(2-furoylamino)imidazo[4,5-c]-pyridine(9), and seven 7-acylaminoimidazo[4,5-c]pyridines, namely 7-propionylaminoimidazo[4,5-c]-pyridine(10), 7-butyrylaminoimidazo[4,5-c]pyridine(11), 7-pentanoylaminoimidazo[4,5-c]pyridine(12), 7-hexanoylaminoimidazo[4,5-c]pyridine(13), 7-benzoylaminoimidazo[4,5-c]pyridine(14), 7-phenylacetylaminoimidazo[4,5-c]pyridine(15), and 7-(2-furoylamino)imidazo[4,5-c]pyridine(16) were synthesized and tested for their cytokinin activity with the tobacco callus bioassay. 2 showed a cytokinin activity at 1 × 10⁻⁸ M and gave a callus yield about 72% of that produced by kinetin at 1 × 10⁻⁶ M. 1, 3 and 8 showed the optimum growth responses in the range of 10⁻⁷−10⁻⁶ M. 4, 5, 7, 9–16 were slightly active. These results support previous reports that a nitrogen atom at the 3-position in the purine ring plays an important role in conferring high cytokinin activity.     

Synthesis and anti-enterovirus activity of new analogues of MDL-860

A series of twelve novel compounds, analogues of antiviral agent MDL-860 were synthesized and their antiviral activity was evaluated in vitro against enteroviruses poliovirus 1 (PV1), Coxsackieviruses B1 (CVB1) and Coxsackieviruses B3 (CVB3). Compounds 14, 24 and 25 manifested strong antiviral effects against CVB1 and PV1 (SI values of 405 and 118 for CVB1 and PV1 respectively). In contrast to the wide anti-enteroviral activity of MDL-860, these three compounds were inactive against CVB3. Compounds 14, 24 and 25 along with MDL-860 were tested in vivo in mice infected with CVB1. Marked protective effects of compounds 14 and 24 were established, PI values of 50% and 33.3%, respectively. In addition, almost all of the tested compounds manifested very low toxicity.     

Design,synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity

A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC₅₀ (FXa) value of 0.14 μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.     

Synthesis and anti-hyperglycemic activity of hesperidin derivatives

A series of hesperidin derivatives were prepared and identified by IR, ¹H NMR, and MS spectra. These compounds were evaluated in vitro and in vivo based on α-glucosidase inhibition, glucose consumption of HepG2 cells, and blood glucose level in streptozotocin-induced diabetic mice. The results revealed that all the compounds exhibited anti-hyperglycemic activities. The inhibition at 10^?3 M of compounds 3 and 7a on α-glucosidase were 55.02% and 53.34%, respectively, as compared to 54.80% by acarbose. Treated by compound 3 and the reference drug metformin, glucose consumption of HepG2 cell were 1.78 and 2.11 mM, respectively. After the streptozotocin-induced diabetic mice were oral administrated with compound 3 at 100 mg kg^?1 d^?1 for 10 days, the blood glucose level of 3 treated mice (13.23 mM, P <0.05) showed significant difference when compared to model control (23.03 mM). Thus, compound 3 exhibited promising anti-hyperglycemic activity.     

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis,biological activity and structure activity relationship of plasmepsin inhibitors

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C₂ symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (K_i, 1.93?±?0.29?µM for Plm II; K_i, 1.99?±?0.05?µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (K_i, 0.84?±?0.08?µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC₅₀, 2.27?±?0.95?µM for 10f; IC₅₀, 3.11?±?0.65?µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC₅₀ value of 1.35?±?0.85?µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.     

Synthesis and proapoptotic activity of oleanolic acid derived amides

Thirty-one different 3-O-acetyl-OA derived amides have been prepared and screened for their cytotoxic activity. In the SRB assays nearly all the carboxamides displayed good cytotoxicity in the low μM range for several human tumor cell lines. Low EC₅₀ values were obtained especially for the picolinylamides 14–16, for a N-[2-(dimethylamino)-ethyl] derivative 27 and a N-[2-(pyrrolinyl)-ethyl] carboxamide 28. These compounds were submitted to an extensive biological testing and proved compound 15 to act mainly by an arrest of the tumor cells in the S phase of the cell cycle. Cell death occurred by autophagy while compounds 27 and 28 triggered apoptosis.     

Antibacterial activity of singly and doubly modified salinomycin derivatives

The increasing challenge of antibiotic resistance stimulates the search for novel antibacterial agents, especially such that would be effective against multi-drug resistant bacterial strains. Fortunately, natural compounds are excellent sources of potentially new drug leads. Particularly interesting in this context are polyether antibiotic salinomycin (SAL) and its semi-synthetic derivatives, as they exhibit large spectrum of bioactivity. We synthesized and evaluated the antibacterial activity of a series of SAL analogs; four singly (2–3, 15, 17) and two doubly modified (16, 18) derivatives were found to show excellent inhibitory activity not only against planktonic Gram(+) bacterial cells, but also towards select strains of methicillin-resistant staphylococci with the MIC values of 1–4 µg mL⁻¹. Of note, the most promising candidates were more effective in preventing bacterial biofilm formation than unmodified SAL and a commonly used antibiotic – ciprofloxacin. Furthermore, we proved that rational modification of C20 hydroxyl of SAL may reduce genotoxic properties of the obtained analogs. Mechanistically, the structure-activity relationship studies suggested that electroneutral transport mechanism could be beneficial in terms of ensuring high antibacterial activity of SAL derivatives.     

Apoptosis-inducing activity of the actin-depolymerizing agent aplyronine A and its side-chain derivatives

Aplyronine A (1) and mycalolide B (2), which are cytotoxic actin-depolymerizing marine macrolides, were revealed to induce apoptosis in human leukemia HL60 cells and human epithelial carcinoma HeLa S₃ cells. Based on these results, actin-depolymerizing compounds were expected to exhibit apoptosis-inducing activity in cancer cells. Compounds 3–6, which were synthesized based on the side-chain structure of aplyronine A, were evaluated for their actin-depolymerizing activities in vitro and cytotoxicities against HL60 cells. The growth-inhibitory activities of 3–6 were well correlated with their actin-depolymerizing activities, and derivative 6 was shown to induce the disruption of actin filaments and apoptosis in HL60 cells. These results suggested that actin-depolymerizing agents 1, 2, and 6-induced apoptosis in HL60 cells may have been due to their actin-depolymerizing activity.     

Synthesis and antiprotozoal activity of 2,5-bis[amidinoaryl]thiazoles

Seven novel diamidino 2,5-bis(aryl)thiazoles (5a–g) were synthesized and evaluated against Trypanosoma brucei rhodensiense (T. b. r.) and Plasmodium falciparum (P. f.). The diamidines were obtained directly from the corresponding bis-nitriles (4a–g) by the action of lithium bis(trimethylsilyl)amide. The bis-nitriles 4a–f were synthesized in four steps starting with the Stille coupling of 2-tributyltinthiazole with the appropriate cyanoaryl halide. The bis-nitrile 5g was obtained by the palladium facilitated coupling of the mixed tin-silyl reagent 2-trimethylsilyl-5-trimethyltinthiazole with 2-bromo-5-cyanopyridine. The amidoxime potential prodrugs 6a–e, 6g were obtained by the reaction of hydroxylamine with the bis-nitriles. O-Methylation of the amidoximes gave the corresponding N-methoxyamidines 7a–c, 7e, 7g. The diamidines showed strong DNA binding affinity as reflected by ΔT_m measurements. Four of the diamidines 5a, 5b, 5d and 5e were highly active in vitro against P. f. giving IC₅₀ values between 1.1 and 2.5 nM. The same four diamidines showed IC₅₀ values between 4 and 6 nM against T. b. r. The selectivity indices ranged from 233 to 9175. One diamidine 5a produced one of four cures at an ip dose of 4 × 5 mg/kg in the STIB900 mouse model for acute African trypanosomiasis. The amidoxime and N-methoxyamidine of 5a were the only produgs to provide cures (1/4 cures) in the same mouse model on oral dosage at 4 × 25 mg/kg.     

Anti-sickling activity of nitrosoureas

Incubation at physiological conditions of erythrocytes from a person bearing the sickle-cell trait with 1-methyl-1-nitrosourea, 1,3-bis-(2-chloroethyl)-1-nitrosourea, or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea prevented sickling of the cells upon subsequent treatment of the cells with sodium metabisulfite. In these experiments these compounds were more effective than potassium cyanate as inhibitors of sickling. It is assumed that the inhibition results from the carbamoylation of the hemoglobin S by the isocyanic acid or the isocyanates derived from the nitrosoureas.     

Synthesis and anti-HIV activity of alkylated quinoline 2,4-diols

Naturally occurring quinolone alkaloids, buchapine (1) and compound 2 were synthesized as reported in literature and evaluated for anti-HIV potential in human CD4+ T cell line CEM-GFP, infected with HIV-1_NL4.3 virus by p24 antigen capture ELISA assay. The compounds 1 and 2 showed potent inhibitory activity with IC₅₀ value of 2.99 and 3.80 μM, respectively. Further, 45 alkylated derivatives of quinoline 2,4-diol were synthesized and tested for anti-HIV potential in human CD4+ T cell line CEM-GFP. Among these, 13 derivatives have shown more than 60% inhibition. We have identified three most potent inhibitors 6, 9 and 23; compound 6 was found to be more potent than lead molecule 1 with IC₅₀ value of 2.35 μM and had better therapeutic index (26.64) as compared to AZT (23.07). Five derivatives 7, 19a, 19d, 21 and 24 have displayed good noticeable anti-HIV activity. All active compounds showed higher CC₅₀ values which indicate that they have better therapeutic indices.     

Synthesis and antimycobacterial activity of calpinactam derivatives

Synthesis of calpinactam 1, a fungal antimycobacterial metabolite, utilizing solid-phase peptide synthesis is described. To explore the structure–activity relationships of 1, its derivatives with different amino acids were also synthesized on the basis of the same synthetic strategy. These derivatives were examined for antimycobacterial activity against Mycobacterium smegmatis. Among them, only peptide 6d having d-Ala in place of d-Glu showed moderate activity.     

Further sesquiterpenoids from the rhizomes of Homalomena occulta and their anti-inflammatory activity

The rhizomes of Homalomena occulta are called Qian-nian-jian in Traditional Chinese Medicine (TCM), which is widely consumed in China owing to its health benefits for the treatment of rheumatoid arthritis and for strengthening tendons and bones. A phytochemical investigation on this famous TCM yielded 19 sesquiterpenoids (1–19) with various carbocyclic skeletons including isodaucane (2, 8, and 9), guaiane (3), eudesmane (4 and 10–15), oppositane (5, 16, and 17), and aromadendrane (18 and 19) types. The structures of new compounds, Homalomenins A-E (1–5), were determined by diverse spectroscopic data. Compound 1 possessed a rare sesquiterpenoid skeleton and compound 5 represented the first example of 1,4-oxa-oppositane sesquiterpenoid. These isolates were evaluated for their inhibitory effects on COX-2 mRNA, COX-2 protein expression, and prostaglandin E2 (PGE2) production in Raw264.7 cells, which demonstrated that compounds 5, 18, 19 showed potent anti-inflammatory activity by suppressing LPS-induced COX-2 expression and PGE2 production in a dose-dependent manner.     

Synthesis and antioxidant activity of thymol and carvacrol based Schiff bases

Thymol and carvacrol are well known antioxidants found in the extract of the plants of thyme species. The Schiff bases of 2-iso-propyl-5-methyl-phenol (thymol/1a), 2-tert-butyl-5-methyl-phenol (1b) and 5-iso-propyl-2-methyl-phenol (carvacrol/1c) exhibited much better antioxidant activity than thymol and carvacrol in DPPH assay. Ten compounds (4k, 4l, 4r, 5k, 5l, 5q, 5r, 6k, 6l and 6r) showed better or similar activity as compared to the reference compound ascorbic acid. Twenty-four most active compounds were also screened by ABTS method and showed 60–90% inhibition at 5 μg/mL concentration.