Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design,synthesis and biological evaluation

A series of novel 2,4-diaminopyrimidine-modified compounds was designed and synthesized. Compound 14 showed micromolar dual inhibitory effect on both FP-2 and PfDHFR, and potential inhibition to the proliferation of P. falciparum 3D7 strain and chloroquine-resistant P. falciparum Dd2 strain.     

Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-d-hexosaminidase and chitinase

Insect chitinase and N-acetyl-β-d-hexosaminidases (Hex) are potential targets for developing new pesticides. Here, a series of thiazolylhydrazones I (with substituted group R₁ at N3) and II (with substituted group R₁ at N2) were designed, synthesised and evaluated as competitive inhibitors of OfHex1 and OfChi-h, from the agricultural pest Ostrinia furnacalis. Derivatives I-3d and II-3d, with phenoxyethyl group at R₁, demonstrated the best inhibitory activities against OfHex1 and OfChi-h. Molecular docking analysis indicated that the branched conformation compound II-3d (K_i = 1.5 μmol/L) formed more hydrogen bonds with OfHex1 than the stretched conformation compound I-3d (K_i = 5.9 μmol/L). The differences in compounds’ binding conformations with OfChi-h explained differences in inhibitory activity of compounds I-3d (K_i = 1.9 μmol/L) and II-3d (K_i = 4.1 μmol/L). This work suggests a novel scaffold for developing specific Hex and Chi-h inhibitors.     

Synthesis and antimicrobial activities of novel quinazolin-4(3H)-one derivatives containing a 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole moiety

A series of novel quinazolin-4(3H)-one derivatives (6a–6y) containing a 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole moiety were designed and synthesized, and their structures were fully characterized by ¹H NMR, ¹³C NMR, HRMS and IR spectra. Among them, the structure of compound 6u was unambiguously confirmed via single crystal X-ray diffraction analysis. The obtained bioassay results showed that compounds 6h, 6k, 6l and 6y had the EC₅₀ (half-maximal effective concentration) values of 34.8, 28.2, 41.5 and 42.5 μg/mL against the phytopathogenic bacterium Xanthomonas oryzae pv. oryzae (Xoo), respectively, which were significantly better than commercial bactericide Bismerthiazol (EC₅₀ = 95.8 μg/mL). Additionally, compounds 6a and 6b exhibited the strong inhibition activity against the pathogen Xanthomonas axonopodis pv. citri (Xac).     

Synthesis and antitumor activity of water-soluble poly(aminoheterocyclic amine)s (I): N,N,N'''',N''''-tetra[2-(4-amino-5-substituted-s-triazol-3-yl sulfanyl)ethyl] -1,4-benzyldiamine salts

Five water-soluble poly(aminoheterocyclic amine)s containing s-triazole ring were synthesized as respective HC1 salts (5a-5e). Biological activities in L1210 (murine leukemia) and Chinese hamster ovary (CHO) cell lines were investigated via IC50 cytotoxicity determinations. The tide compounds represented moderate cytotoxicity (low IC50 values between 15 and 68μmol/L) in L1210 but high cytotoxicity (lower IC50 values: 0.25,0.018,0.014μmol/L for Sa-5e, respectively) in CHO cell lines, while the corresponding HC1 salts of the intermediates (3a-3e) without polyamine tether and starting materials amino-s-triazoles (1a-1e) showed poor or no activities against the above cell lines.     

Design, synthesis and antiproliferative activities of novel 5H-pyridazino[4,5-b]indoles

A novel series of 5H-pyridazino[4,5-b]indoles were designed and synthesized in order to find novel potent anticancer compounds.The structures were confirmed by ~1H NMR and MS.Their antiproliferative activities against two cancer cell lines were tested by the MTT method in vitro.Three of compounds (1e,1g,and 1h) exhibited potent antiproliferative activities,especially compound 1h (with IC_(50) values of 5.2μmol/L and 1.9μmol/L against Bel-7402 and HT-1080,respectively).The preliminary structure-activity relationships of 5H-pyridazino[4,5-b]indole derivatives were discussed.     

trans-Aconitic acid-based hetero-Diels-Alder reaction in the synthesis of thiopyrano[2,3-d][1,3]thiazole derivatives

The hetero-Diels-Alder reaction of 5-arylideneisorhodanines with trans-aconitic acid proceeds as a regio- and diastereoselective process with spontaneous decarboxylation of the [4+2]-adduct to furnish thiopyrano[2,3-d][1,3]thiazole (2) and chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazole (3) derivatives analogously to the use of itaconic acid as a dienophile. Conversely, the one-pot, three-component reaction of 5-arylideneisorhodanines, trans-aconitic acid and anilines proceeded without decarboxylation, leading to novel rel-(5′R,6′R,7′R)-5′-carboxy-7′-aryl-1-aryl-3′,7′-dihydro-2H,2′H,5H-spiro[pyrrolidin-3,6′-thiopyrano[2,3-d]thiazol]-2,2′,5-triones 4. Interestingly, the use of trans-aconitic acid trimethyl ester led to the opposite regioselectivity, yielding rel-(5R,6S,7S)-5-methyloxycarbonylmethyl-2-oxo-7-aryl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-5,6-dicarboxylates 5. Selected compounds were examined for trypanocide activity against the bloodstream forms of Trypanosoma brucei where compound 4e showed the highest activity (IC₅₀ = 6.74 μM).     

Diterpenoids from the aerial parts of Leonurus macranthus

One cis clerodane-type (1) and three highly oxygenated labdane-type diterpenes (2-4) were isolated from the aerial parts of Leonurus macranthus. Compound 1 represents the first example of cis clerodane-type diterpene in the plants of Leonurus genus.     

A new cytotoxic salannin-class limonoid alkaloid from seeds of Azadirachta indica A. Juss

Azadiramide A (1), a new salannin-class limonoid alkaloid, inhibits growth of human breast cancer MDA-MB-231 cell line with IC₅₀ value of 2.70±0.63 μmol/L.     

Synthesis,characterization and cytotoxic investigations of novel bis(indole) analogues besides antimicrobial study

Two series of novel bis(indole) analogues viz., N′-((5-substituted-1H-indol-3-yl)methylene)-n-(1H-indol-3-yl)alkanehydrazides (7a–f) and N′-((5-substituted-1-(3-methylbut-2-enyl)-1H-indol-3-yl)methylene)-n-(1H-indol-3-yl)acetohydrazide (8a–f) were synthesized and characterized by spectral analysis. The target molecules were screened for their antimicrobial, anticancer activities and structure and activity relationship (SAR) was investigated. Compounds 7a, 7c and 8a were found to be active in antimicrobial screening. Anticancer screening reveals that Compound 7c was active against HeLa cell line with an IC₅₀ of 43.1 μM and compound 7d was found to be interesting candidate with an IC₅₀ of 26.0 and 30.2 μM against Colo-205 and Hep G2 cell lines respectively.     

Bistachybotrysins D and E,one stereoisomeric pair of cytotoxic phenylspirodrimane dimers from Stachybotrys chartarum

Bistachybotrysins D and E (1 and 2), one stereoisomeric pair of phenylspirodrimane dimers, were isolated from Stachybotrys chartarum CGMCC 3.5365. They represent novel phenylspirodrimane dimers with a central [6,5,6]-tricyclic carbon scaffold containing a cyclopentanone core. The structures of 1 and 2 were elucidated through extensive spectroscopic data analysis, and their absolute configurations were characterized by calculated electronic circular dichroism (ECD). Compounds 1 and 2 displayed potent cytotoxic activity against the four human tumor cell lines HCT116, BGC823, Daoy and HepG2 with IC_ (50)values ranging from 6.7 μmol/L to 11.6 μmol/L. Furthermore, a plausible biogenetic pathway for 1 and 2 is proposed.     

Stereoselective synthesis of novel tetrahydroxypyrrolizidines

N-Benzyloxycarbonyl-2,5-dideoxy-2,5-imino-3,4-O-isopropylidene-l-ribose 12a has been converted into (1R,2S,6R,7S,7aS)-5 and (1R,2S,6S,7R,7aR)-1,2,6,7-tetrahydroxypyrrolidin-5-ones 6 and (1R,2S,6S,7S,7aS)-7 and (1R,2S,6R,7R,7aS)-1,2,6,7-tetrahydroxypyrrolizidines 8 following stereoselective paths. These new compounds have been assayed for their inhibitory activities towards 25 glycosidases. Pyrrolizidines 7 and 8 are moderate but selective inhibitors of amyloglucosidase from Rhizopus mold (7: IC₅₀=130 μM, K_i=120 μM; 8: IC₅₀=200 μM, K_i=180 μM, mixed type of inhibition).     

Synthesis and antiviral bioactivity of novel chalcone derivatives containing purine moiety

A series of novel chalcone derivatives containing purine group was synthesized and evaluated for their antiviral activities against cucumber mosaic virus and tobacco mosaic virus. Compound 3o exhibited remarkable antiviral activities and strong combining capacity to tobacco mosaic virus coat protein.     

Synthesis and combined properties of novel fluorinated cationic surfactants derived from hexafluoropropylene dimer

Three novel fluorinated surfactants with branched short fluorinated tails as hydrophobic groups, ammonium oxide as polar groups are prepared. Surface tension measurement shows that these fluorinated surfactants are ideal compounds to design new formulations in fire-fighting field.     

Design,synthesis and biological evaluation of quinazolin-4(3H)-one Schiff base conjugates as potential antiamoebic agents

In an effort to develop novel antiamoebic scaffolds having better efficacy than the standard drug metronidazole (IC₅₀ = 1.80 μM) used against Entamoeba histolytica, quinazolin-4(3H)-one Schiff base conjugates were synthesized and evaluated against HM1: IMSS strain of E. histolytica. Out of the thirteen compounds (S2-S14), six compounds (S2, S3, S4, S5, S6 and S11) were found to be better inhibitors than metronidazole and showed low cytotoxicity on HeLa cells, a cervical cancer cell line. The structure of intermediate compound S1 was confirmed by crystal structure studies.     

Tetracyclic triterpenoids isolated from semi-mangrove plant Hibiscus tiliaceus

A continuing phytochemical study on the semi-mangrove plant Hibiscus tiliaceus yielded two new tetracyclic triterpenoids （3β,24S）-19（10→9）-abeo-8α,9β,10α-eupha-5,25（26）-dien-3,24-diol （tiliacol A, 1 ）, and （3β,23Z）-19（10→9）-abeo-8α,9β,10α-tircalla-5,23-dien-3,25-diol （tiliacol B, 3）, together with one known analog （2）. Their structures were elucidated on the basis of extensive spectral analyses （MS, IR, 1D NMR and 2D NMR） and comparison with literature compounds. Compound 2 showed potent cytotoxicity against both P388 and HeLa cells with ICon values of 11.2 μmol/L and 11.5 μmol/L, resoectively.     

Synthesis,characterization and biological evaluation of purine nucleoside analogues

We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, ¹H NMR, ¹³C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC₅₀ value of 7.9, 6.8 µg/mL respectively against MDA-MB-231 and of 7.5, 8.3 µg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.     

Gold-catalyzed oxazoles synthesis and their relevant antiproliferative activities

Nine 5-aryl-2-methyloxazole derivatives were synthesized via gold-catalyzed alkyne oxidation. All of the compounds have been screened for their antiproliferative activities against MCF-7 cell （human breast carcinoma）, A549 cell （human lung carcinoma） and Hela cell （human cervical carcinoma） lines in vitro. The results revealed that compounds 1b, 1c and 1d exhibited strong inhibitory activities against the MCF-7 cell lines （with ICso values of 4.6, 9.7 and 2.2 μmol/L, respectively）.     

Design,synthesis, and fungicidal activity of novel 1,3,4-oxadiazole derivatives

Employing the intermediate derivatization method (IDM), a series of 1,3,4-oxadiazole derivatives containing arylpyrazoloxyl moiety were designed and synthesized. In vitro bioassays showed that these compounds have moderate to significant fungicidal activity against rice sheath blight and sorghum anthracnose. Furthermore, compound 20 is a promising fungicide for further development.     

New compounds from the roots of Coriaria nepalensis

One new sesquiterpene lactone possessing novel variations in the structure, corialactone E (1), one new neolignan, coriarianeolignan A (2), together with three known apocarotenoids (3-5) and one known neolignan (6), have been isolated from a CHCl₃ extract of the roots of Coriaria nepalensis.     

Synthesis and molecular modeling study of Cu(Ⅱ) complexes derived from 2-(diphenylmethylene)hydrazinecarbothioamide derivatives with cholinesterase inhibitory activities

Thiosemicarbazones of 2-amino-5-chlorobenzophenone and 3-aminobenzophenone（L¹-L⁴） have been synthesized and their Cu（Ⅱ） complexes（1-4） were afforded via coordination with cupric chloride.All these compounds were characterized by UV-vis and IR spectroscopy together with CHN elemental analysis.NMR spectroscopy was also applied to characterize the ligands.In vitro chohnesterase inhibitory assays for the complexes（1-4） showed IC₅₀ values less than 10μmol/L,with complex 1 exhibiting the most activity,IC₅₀=2.15μmol/L and 2.16μmol/L for AChE and BuChE,respectively. Molecular modeling simulation revealed the binding interaction template for complex 1 with the AChE and BuChE receptors.In DPPH assay,the complexes also showed more in vitro antioxidant activities in comparison to their parent ligands.