Project description:We recently identified fingolimod as a potent antibiofilm compound by screening FDA-approved drugs. To study if the antibacterial activity of fingolimod could be further improved and to explore in-depth structure-activity relationships, we synthesized 28 novel fingolimod derivatives and evaluated their efficacy against Staphylococcus aureus grown in planktonic/single cell and biofilms. The most effective derivatives were tested on preformed S. aureus biofilms and against Gram-negative bacteria Acinetobacter baumannii and Pseudomonas aeruginosa, using fingolimod as the reference compound. Seven derivatives were more effective against S. aureus, while five other derivatives showed improved activity against P. aeruginosa and/or A. baumannii, with no apparent change in cytotoxicity on human cells. The most interesting derivatives, compounds 43 and 55, displayed a broader spectrum of antibacterial activity, possibly exerted by the change of the para-hydrocarbon chain to a meta position for 43 and by an additional hydroxyl group for 55.
Project description:The mammalian transient receptor potential melastatin channel 8 (TRPM8), highly expressed in trigeminal and dorsal root ganglia, mediates the cooling sensation and plays an important role in the cold hypersensitivity characteristic of some types of neuropathic pain, as well as in cancer. Consequently, the identification of selective and potent ligands for TRPM8 is of great interest. Here, a series of compounds, having a β-lactam central scaffold, were prepared to explore the pharmacophore requirements for TRPM8 modulation. Structure-activity studies indicate that the minimal requirements for potent β-lactam-based TRPM8 blockers are hydrophobic groups (benzyl preferentially or t Bu) on R1, R2, R3 and R5 and a short N-alkyl chain (≤3 carbons). The best compounds in the focused library (41 and 45) showed IC50 values of 46 nM and 83 nM, respectively, in electrophysiology assays. These compounds selectively blocked all modalities of TRPM8 activation, i.e. menthol, voltage, and temperature. Molecular modelling studies using a homology model of TRPM8 identified two putative binding sites, involving networks of hydrophobic interactions, and suggesting a negative allosteric modulation through the stabilization of the closed state. Thus, these β-lactams provide a novel pharmacophore scaffold to evolve TRPM8 allosteric modulators to treat TRPM8 channel dysfunction.
Project description:P2Y6 receptor (P2Y6R) antagonists represent potential drugs for treating cancer, pain, neurodegeneration, asthma, diabetes, colitis and other disorders. However, there are few chemical classes of known competitive antagonists. We recently explored the structure activity relationship (SAR) of 2H-chromene derivatives as P2Y6R antagonists of moderate affinity. New analogues in this series modified at five positions were synthesized and shown to antagonize Ca2+ transients induced by the native agonist UDP in human (h) P2Y6R-expressing (but not turkey P2Y1R-, hP2Y2R- or hP2Y4R-expressing) astrocytoma cells. Alternatives to the reported 2-(trifluoromethyl)- and 3-nitro- substitutions of this scaffold were not identified. However, 6‑fluoro 11 and 6‑chloro 12 analogues displayed enhanced potency compared to other halogens, although still in the 1 - 2 µM range. Similar halogen substitution at 5, 7 or 8 positions reduced affinity. 5- or 8‑Triethylsilylethynyl extension maintained hP2Y6R affinity, with IC50 0.46 µM for 26 (MRS4853). The 6,8‑difluoro analogue 27 (IC50 2.99 µM) lacked off-target activities among 45 sites examined, unlike earlier analogues that bound to biogenic amine receptors. 11 displayed only one weak off-target activity (σ2). Mouse P2Y6R IC50s of 5, 25, 26 and 27 were 4.94, 17.6, 6.15 and 17.8 µM, respectively, but most other analogues had reduced affinity (>20 µM) compared to the hP2Y6R. These analogues are suitable for evaluation in in vivo inflammation and cancer models, which will be performed in the future studies.
Project description:By using a fragment-assembly strategy and bioisosteric-replacement principle, a series of novel piperazine derivatives were designed, synthesized, and evaluated for their cellular target-effector fusion activities and in vitro antiviral activities against HIV-1. Preliminary structure-activity relationships (SARs) of target compounds were concluded in this study, and five compounds were found to exhibited medium to potent CCR5 fusion activities with IC(50) values in low micromolar level. Among evaluated compounds, 23 h was found to be a CCR5 antagonist with an IC(50) value of 6.29 µM and an anti-HIV-1 inhibitor with an IC(50) value of 0.44 µM.
Project description:The paper presents synthesis and characterization of nine new thiazolyl-(phenyldiazenyl)-2H-chromen-2-one dyes. The impact of substituent structure in thiazole ring in the synthesized azocoumarin derivatives on electrochemical properties, photoisomerization process and photovoltaic response was examined. The dyes were electrochemically active and undergo reduction and oxidation processes. They showed low electrochemically estimated energy band gap in the range of 1.71-2.13 eV. Photoisomerization process of the synthesized molecules was studied in various solvents such as ethanol, chloroform and N,N-dimethylformamide (DMF) upon the UV illumination. It was found that novel azodyes showed reversible trans-cis-trans isomerization and exhibited long thermal back to the trans form, that was even 7 days in DMF. Selected azocoumarin were molecularly dispersed in polystyrene for preparation of guest-host azopolymer systems to study the cis-trans thermal isomerization of obtained dyes in solid state. The photovoltaic activity of the azochromophores was tested in bulk-heterojunction solar cells. They acting as weak donors in device with structure ITO/PEDOT:PSS/dye:PC70BM/Al. No photovoltaic response of cells with azocoumarin derivatives bearing 4-fluorobenzene, 3,4-dichlorobenzene, or 4-(1-adamantyl) unit was found. Additionally, dye which showed the best activity was examined in three-component solar cells ITO/PEDOT:PSS/PTB7:PC70BM:dye/PFN/Al.
Project description:We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 ?M), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 ?M), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 ?M). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.
Project description:Prostate cancer is one of the malignant tumors and the second most common malignant tumor in men. Clinically used androgen receptor (AR)–targeted drugs can antagonize androgen and inhibit tumor growth, but these drugs can cause serious resistance problems. To develop novel AR antagonists, 22 kinds of arylpiperazine derivatives were designed and synthesized, and the derivatives 5, 8, 12, 19, 21, 22, 25, and 26 not only showed strong antagonistic potency (>55% inhibition) and binding affinities (IC50 <3 μM) to AR, but also showed stronger inhibitory activity to LNCaP cells versus PC-3 cells. Among them, derivative 21 exhibited the highest binding affinity for AR (IC50 = 0.65 μM) and the highest antagonistic potency (76.2% inhibition). Docking studies suggested that the derivative 21 is primarily bound to the AR-LBP site by the hydrophobic interactions. Overall, those results provided experimental methods for developing novel arylpiperazine derivatives as potent AR antagonists.
Project description:An agonist-antagonist switching strategy was performed to discover novel PPARα antagonists. Phenyldiazenyl derivatives of fibrates were developed, bearing sulfonimide or amide functional groups. A second series of compounds was synthesized, replacing the phenyldiazenyl moiety with amide or urea portions. Final compounds were screened by transactivation assay, showing good PPARα antagonism and selectivity at submicromolar concentrations. When tested in cancer cell models expressing PPARα, selected derivatives induced marked effects on cell viability. Notably, 3c, 3d, and 10e displayed remarkable antiproliferative effects in two paraganglioma cell lines, with CC50 lower than commercial PPARα antagonist GW6471 and a negligible toxicity on normal fibroblast cells. Docking studies were also performed to elucidate the binding mode of these compounds and to help interpretation of SAR data.
Project description:Prostate cancer (PCa) is a malignant tumor with a higher mortality rate in the male reproductive system. In this study, the hydroxyazine derivatives were synthesized with different structure from traditional anti-prostate cancer drugs. In the evaluation of in vitro cytotoxicity and antagonistic activity of PC-3, LNCaP, DU145 and androgen receptor, it was found that the mono-substituted derivatives on the phenyl group (4, 6, 7, and 9) displayed strong cytotoxic activities, and compounds 11-16 showed relatively strong antagonistic potency against AR (Inhibition% >55). Docking analysis showed that compounds 11 and 12 mainly bind to AR receptor through hydrogen bonds and hydrophobic bonds, and the structure-activity relationship was discussed based on activity data. These results suggested that these compounds may have instructive implications for drug structural modification in prostate cancer.
Project description:The design, synthesis and structure-activity relationship studies of some novel trisubstituted pyrimidine amide derivatives prepared as CCR4 antagonists are described. The activities of these compounds were evaluated by the CCR4-MDC chemotaxis inhibition assay. Compound 1, which we have previously reported as a potent antagonist of CCR4, was employed as the positive control. The results indicated that most of the synthesized compounds exhibited some chemotaxis inhibition activity against CCR4. Of these new compounds, compounds 6c, 12a and 12b, with IC₅₀ values of 0.064, 0.077 and 0.069 μM, respectively, showed higher or similar activity compared with compound 1 (IC₅₀ of 0.078 μM). These compounds provide a basis for further structural modifications. The systematic structure-activity relationship of these trisubstituted pyrimidine amide derivatives was discussed based on the obtained experimental data. The results from the SAR study may be useful for identifying more potent CCR4 antagonists.