Project description:Human African trypanosomiasis (HAT) is a deadly neglected tropical disease caused by the protozoan parasite Trypanosoma brucei. During the course of screening a collection of diverse nitrogenous heterocycles, we discovered two novel compounds that contain the tetracyclic core of the Yohimbine and Corynanthe alkaloids, were potent inhibitors of T. brucei proliferation and T. brucei methionyl-tRNA synthetase (TbMetRS) activity. Inspired by these key findings, we prepared several novel series of hydroxyalkyl δ-lactam, δ-lactam, and piperidine analogs and tested their anti-trypanosomal activity. A number of inhibitors are more potent against T. brucei than these initial hits with one hydroxyalkyl δ-lactam derivative being 25-fold more effective in our assay. Surprisingly, most of these active compounds failed to inhibit TbMetRS. This work underscores the importance of verifying, irrespective of close structural similarities, that new compounds designed from a lead with a known biological target engage the putative binding site.
Project description:A highly diastereoselective method for the synthesis of novel spiro-tetrahydroquinoline derivatives is reported here, using a one-pot reaction method. All compounds were characterized by 1H-nuclear magnetic resonance (NMR) and mass spectroscopy, and their stereo configurations were confirmed by X-ray analysis. These activities of these derivatives were then tested in human keratocyte cells. The responses of cells to treatment with selected compounds were studied using scratch analysis, and the compounds were tested in a mouse excision wound model. Three of the derivatives demonstrated significant wound-healing activities.
Project description:Sepsis, an acute inflammatory disease, remains the most common cause of death in intensive care units. A series of benzimidazole and imidazopyridine derivatives were synthesized and screened for anti-inflammatory activities, and the imidazopyridine series showed excellent inhibition of the expression of inflammatory cytokines in LPS-stimulated macrophages. Compounds X10, X12, X13, X14, and X15 inhibited TNF-? and IL-6 release in a dose-dependent manner, and X12 showed no cytotoxicity in hepatic cells. Furthermore, X12 exhibited a significant protection against LPS-induced septic death in mouse models. Together, these data present a series of new imidazopyridines with potential therapeutic effects in acute inflammatory diseases.
Project description:A series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against both fluconazole-sensitive and -resistant Candida albicans cells and had potent inhibition activity against Candida albicans biofilm formation and hyphal growth. Moreover, C38 showed good synergistic antifungal activity in combination with fluconazole (FLC) against FLC-resistant Candida species. Preliminary mechanism studies revealed that C38 might act by inhibiting the synthesis of fungal cell wall.
Project description:We have previously demonstrated that DCB-3503, a tylophorine analogue, has an anti-inflammatory property in murine models for autoimmune diseases. However, its mechanism remains unknown. Here, we have synthesized 34 derivatives of DCB-3503 and investigated their effects on T cells differentiation and TNF-? production. Six derivatives (4, 9, 13, 19, 31, and 32) could significantly promote the expression of Foxp3. Among these, the IC50 of 31 and 32 was about 500 ?M. Eight analogues (1, 2, 4, 9, 12, 18, 19, and 21) showed anti-TNF-? effect in Raw 264.7 cells and murine splenocytes, of which 18 and 19 were most significant. Moreover, 31 and 18 showed a better activity and cell survival ratio when compared with DCB-3503 at various concentrations. In summary, we have demonstrated the anti-inflammatory characteristics of 34 novel tylophorine derivatives and discussed their structure-activity relationship in order to explore their therapeutic potentials for inflammatory diseases.
Project description:The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.
Project description:This study aims to synthesize novel fused spiro-4H-pyran derivatives under green conditions to develop agents having antimicrobial activity. The synthesized compounds were initially screened for in vitro antibacterial activity against two Gram-positive and three Gram-negative bacterial strains, and all the compounds exhibited moderate to potent antibacterial activity. However, compound 4l showed significant inhibition toward all the bacterial strains, particularly against Streptococcus pneumoniae and Escherichia coli with minimum inhibitory concentration values of 125 μg/mL for each. The toxicity studies of selected compounds (4c, 4e, 4l, and 4m) using human red blood cells as well as human embryonic kidney (HEK-293) cells showed nontoxic behavior at desired concentration. Growth kinetic and time-kill curve studies of 4l against S. pneumoniae and E. coli supported its bactericidal nature. Interestingly, compound 4l showed a synergistic effect when used in combination with ciprofloxacin against selected strains. Biofilm formation in the presence of a lead compound, as assessed by XTT assay, showed complete disruption of the bacterial biofilm visualized by scanning electron microscopy. Overall, the findings suggest 4l to be considered as a promising lead for further development as an antibacterial agent.
Project description:Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 ?M, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 ?M). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 ?M, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC50 (Vero cells) ? 227 ?M], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.
Project description:Here, we explored in detail an acid-catalyzed condensation of glyoxylic acid or its ethyl ester with several carboxamides of different basicity, or with mesyl amide, to furnish diaminoacetic acid derivatives. The most suitable synthesis conditions and the reaction catalysts were identified. Properties such as structure and basicity of the starting amides were demonstrated to influence the condensation process. Elemental iodine was used for the first time herein as an acid catalyst for the condensation of glyoxylic acid or its ester, which gave access to diaminoacetic acid derivatives in higher yields in most cases, as opposed to p-toluenesulfonic acid (PTSA). An abnormally high activity of mesyl amide when condensed with ethyl glyoxylate was noticed, which may evidence a special impact of the sulfonyl moiety in the amide molecule on the condensation.
Project description:A series of structurally diverse 4-bromo spiro-isoxazolines possessing a variety of aromatic and aliphatic substituents at the 3 position, were synthesized through a 1,3-dipolar cycloaddition followed by intramolecular cyclization of a pendant hydroxyl or carboxylic acid group. The biochemical antiproliferative activity was evaluated in vitro by using two breast cancer cell lines (MCF-7 and MDA-MB-231) and two prostate cancer cell lines (PC-3 and DU-145) using the MTT viability assay, and the IC50 values were obtained. Spiro-isoxazoline derivatives bearing a p-chloro or an o-dichloro aromatic substituent at the 3-position of the isoxazoline showed considerable antitumor activities in all four cell lines with IC50 value ranging from 43?M to 56?M.