Synthesis of 3,5-Bis(trifluoromethyl)phenyl-Substituted Pyrazole Derivatives as Potent Growth Inhibitors of Drug-Resistant Bacteria.

Enterococci and methicillin-resistant S. aureus (MRSA) are among the menacing bacterial pathogens. Novel antibiotics are urgently needed to tackle these antibiotic-resistant bacterial infections. This article reports the design, synthesis, and antimicrobial studies of 30 novel pyrazole derivatives. Most of the synthesized compounds are potent growth inhibitors of planktonic Gram-positive bacteria with minimum inhibitory concertation (MIC) values as low as 0.25 µg/mL. Further studies led to the discovery of several lead compounds, which are bactericidal and potent against MRSA persisters. Compounds 11, 28, and 29 are potent against S. aureus biofilms with minimum biofilm eradication concentration (MBEC) values as low as 1 µg/mL.

Angiokinase inhibition of VEGFR-2, PDGFR and FGFR and cell growth inhibition in lung cancer: Design, synthesis, biological evaluation and molecular docking of novel azaheterocyclic coumarin derivatives.

The present work represents the design and synthesis of some azaheterocyclic coumarin derivatives which are evaluated as anti-lung cancer agents. Ten out of the twenty azaheterocyclic compounds showed superior activity than the standard drug staurosporine against non-small cell lung cancer (A549). Representing the four different azaheterocyclic series, compounds 4a, 5d, 6e, and 7d, which demonstrated IC50s of 2.38, 2.39, 1.05 and 3.98 µM, respectively, each exhibiting the best cytotoxicity in its group, were selected for further assessment of their toxicity on normal lung cells (WI-38). Compound 4a was selected for further investigations because it remarkably revealed less cytotoxicity (IC50 = 53.76 µM) than 7d (IC50 = 19.95 µM) on (WI-38) compared to staurosporine (IC50 = 24.41 µM). 4a was assessed for its ability to inhibit the angiokinases VEGFR-2, PDGFR, FGFR and the growth factor EGFR, remarkably it showed better VEGFR-2, PDGFR, FGFR inhibition than the reference drugs used and exhibited as well noticeable EGFR inhibition. Going further, 4a was capable of arresting the cell cycle at pre-G1 phase and S phase and inducing apoptosis. Moreover, the capability of the target 4a to interact with the key amino acids of VEGFR-2 binding site was detected by molecular docking. Finally, the in silico physicochemical properties of 4a were studied.

Evaluation of Chalcone Derivatives as Photosynthesis and Plant Growth Inhibitors.

We report the evaluation of chalcone derivatives as photosystem II (PSII) and plant growth inhibitors. Chalcone derivatives were evaluated as PSII inhibitors through Chl a fluorescence measurement. (E)-Chalcone (6a) and (E)-3-(4-bromophenyl)-1-(4-fluorophenyl)prop-2-en-1-one (6j) showed the best results, reducing the performance index on absorption basis parameter (PIabs ) by 70 %. Additionally, the decrease of TR0 /RC and ET0 /RC parameters indicates that the chalcone derivatives limited the number of active PSII reaction centers and the amount of trapped energy within them. Compounds 6a and 6j both act as post-emergent herbicides at 50 µM, reducing the root biomass of the Ipomoea grandifolia weed by 72 % and 83 %, respectively, corroborating the fluorescence results. The selectivity against weeds as compared to valuable crops by compounds 6a and 6j were evaluated employing Zea mays and Phaseolus vulgaris plants. In these, our newly synthesized compounds showed no effects on biomass accumulation of roots and aerial parts when compared to the control, providing valuable evidence for the role of these compounds as selective inhibitors of the growth of undesired weeds.

Derivatives of 1,2,4-triazole imines acting as dual iNOS and tumor cell growth inhibitors.

A set of 4-(R2-imino)-3-mercapto-5-(R1)-4H-1,2,4-triazoles derivatives were synthesized, characterized and evaluated for their ability to inhibit nitric oxide (NO) production in PAM212 mouse keratinocytes, which led to the discovery and the subsequent evaluation of their growth inhibitory cytotoxic potency toward that same mouse cell line together with a number of human cells lines (PC3, HT-29 and HeLa). Some limited SAR could be established for both NO production inhibition potency and growth inhibition cytotoxicity. Noticeably, the compounds designed to be nitrofurantoin mimics were the most potent anti-neoplastic agents.

Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors.

The identification of a new series of growth inhibitors of Trypanosoma cruzi, the causative agent of Chagas' disease, is described. In vitro screening of a subset of compounds from our in-house compound collection against the parasite led to the identification of hit compound 1 with low micromolar inhibition of T. cruzi growth. SAR exploration on the hit compound led to the identification of compounds that show nanomolar parasite growth inhibition (T. cruzi EC50 ≤ 100 nM) and no cytotoxicity in human cells (HeLa CC50 > 50 µM). Further investigation identified CYP51 inhibition (compound 11 CYP51 IC50 52 nM) as a possible mechanism of action of this new class of anti-parasitic agents.

Synthesis and evaluation of indole derivatives as photosynthesis and plant growth inhibitors.

Indole derivatives were synthetized based on the Fischer indole methodology using different phenyl hydrazine hydrochlorides and either cyclohexanone or 2-butanone. The pre- and post-emergent herbicidal activities were evaluated against Ipomoea grandifolia. A carbazole, 6-chloro-2,3,4,9-tetrahydro-1H-carbazole (3b), decreased the PIabs parameter by 32% and increased the cross-section related parameters, indicating the inactivation of the reaction center on photosystem II. Compound 3b acts as a post-emergent herbicide prototype since dry biomass was reduced by 50%, corroborating the fluorescence results. Comparing instead with a germination experiment, 2,3,4,9-tetrahydro-1H-carbazole (3a) was found to be the most effective agent, inhibiting seed germination by 22% and decreasing root length by 50%. The tetrahydrocarbazoles showed better results than indole derivatives potentially due to the presence of methylene groups at structures, which increase the compounds' lipophilicity and may facilitate their access to the plant. In addition, electron withdrawing groups on the aromatic ring were found to correlate with increased herbicide activity. Further optimization of this series towards the development of herbicides is ongoing.

Identification of Novel Human Breast Carcinoma (MDA-MB-231) Cell Growth Modulators from a Carbohydrate-Based Diversity Oriented Synthesis Library.

The application of a cell-based growth inhibition on a library of skeletally different glycomimetics allowed for the selection of a hexahydro-2H-furo[3,2-b][1,4]oxazine compound as candidate inhibitors of MDA-MB-231 cell growth. Subsequent synthesis of analogue compounds and preliminary biological studies validated the selection of a valuable hit compound with a novel polyhydroxylated structure for the modulation of the breast carcinoma cell cycle mechanism.

Synthesis and Characterization of a Walnut Peptides-Zinc Complex and Its Antiproliferative Activity against Human Breast Carcinoma Cells through the Induction of Apoptosis.

The walnut peptides and zinc ions were combined to generate a walnut peptides-zinc complex (WP1-Zn) with enhanced antiproliferative ability as well as reduced toxicity. The result indicated that Zn ions were successfully combined with WP1 through Zn-N and Zn-O covalent bonds. WP1-Zn compounds exhibited strong antiproliferative ability against the selected human cell lines, especially MCF-7 cells, whose survival rate reduced to 20.02% after exposure to 300 µg/mL of WP1-Zn for 48 h. WP1-Zn inhibited MCF-7 cell proliferation through inducing cell apoptosis and cell cycle arrest. The results indicated that WP1-Zn induced MCF-7 cell apoptosis via the ROS triggered mitochondrial-mediated pathway and cell surface receptor-mediated pathway. Our work is the first attempt to elucidate the synergic effect of novel walnut peptides and Zn and with the hope of better understanding the antiproliferative action of bioactive peptides and a zinc complex and support the potential application of WP1-Zn as a functional food ingredient or complementary medicine.

Enantioselective synthesis of dictyoceratin-A (smenospondiol) and -C, hypoxia-selective growth inhibitors from marine sponge.

Total syntheses of (+)-dictyoceratin-C (1) and (+)-dictyoceratin-A (smenospondiol) (2), hypoxia-selective growth inhibitors isolated from marine sponge, were executed. The absolute stereochemistry of the each compound was determined through the enantioselective total syntheses of them. It revealed that the unnatural enantiomers of them also exhibited the hypoxia-selective growth inhibitory activity against human prostate cancer DU-145 cells.

Synthesis of methyl 2-cyano-3,12-dioxo-18ß-olean-1,9(11)-dien-30-oate analogues to determine the active groups for inhibiting cell growth and inducing apoptosis in leukemia cells.

Fourteen of the methyl 2-cyano-3,12-dioxo-18ß-olean-1,9(11)-dien-30-oate (CDODO-Me-12, 10d) analogues with different structures of ring C were synthesized to determine the active groups for inhibiting cell growth and inducing apoptosis in human leukemia HL-60 cells. An unsaturated group in ring C was required to maintain the ability to inhibit cell growth and induce apoptosis. Compound 10e with 9(11),12-dien in ring C displayed comparable apoptosis induction ability to 10d associated with decreased levels of c-FLIP, but not Mcl-1 and XIAP. Compound 10e had decreased ability to deplete GSH compared to compound 10d. Compound 10e represents a new active compound acting through a different mechanism from that of compound 10d.