New Promising Compounds with in Vitro Nanomolar Activity against <i>Trypanosoma cruzi</i>

The antiparasitic activity of azole and new 4-aminopyridine derivatives has been investigated. The imidazoles <b>1</b> and <b>3</b>–<b>5</b> showed a potent in vitro antichagasic activity with IC₅₀ values in the low nanomolar concentration range. The (<i>S</i>)-<b>1</b>, (<i>S</i>)-<b>3</b>, and (<i>S</i>)-<b>5</b> enantiomers showed (up to) a thousand-fold higher activity than the reference drug benznidazole and furthermore low cytotoxicity on rat myogenic L6 cells

Cell cycle.

<p>HEK293 cells stably expressing Pdcd4_(39–91)luc were incubated for 24 h with DMSO (blue) or increasing concentrations of compounds <b>1</b>, <b>2</b>, <b>3</b>, <b>4</b>, <b>5</b>, and <b>6</b> (3 μM (violet), 10 μM (yellow), and 30 μM (red)). Cell cycle analysis was performed after permeabilization using 7-AAD. Data are presented as means ± SEM of at least 3 independent experiments (* p<0.05, ** p<0.01, *** p<0.01).</p

Conformational analysis of compounds 1, 2 and 4.

<p>(A) A systematic approach was chosen to explore the conformational space around the three rotable bonds. (B-D) Global minimum energy conformations (<i>left panel</i>) and energy plots (<i>right panel</i>) of compounds <b>1</b> (B), <b>2</b> (C), and <b>4</b> (D).</p

Pdcd4 stabilizing activity.

<p>HEK293 cells stably expressing the Pdcd4 stability reporter Pdcd4_(39–91)luc were incubated for 8 h with TPA [10 nM] in combination with increasing concentrations (0.1–30 μM) of compounds <b>1</b>, <b>2</b>, <b>3</b>, <b>4</b>, <b>5</b>, and <b>6</b>. Pdcd4 stabilizing activity was determined relative to Δ(RLU_DMSO–RLU_TPA). Data are presented as means ± SEM of at least 3 independent experiments (* p<0.05, ** p<0.01, *** p<0.01).</p

Chemical structures.

<p>Structures of compounds <b>1</b> (1,2-bis(4-chlorophenyl)disulfide), <b>2</b> (4-chloro-<i>N</i>-(4-chlorophenyl)benzamide), <b>3</b> ((<i>E</i>)-1,2-bis(4-chlorophenyl)diazene), <b>4</b> (1,2-bis(4-chlorophenyl)hydrazine), <b>5</b> (1,2-bis(4-methoxyphenyl)disulfide), and <b>6</b> (1,2-bis(4-nitrophenyl)disulfide).</p

Proliferation.

<p>HEK293 cells stably expressing Pdcd4_(39–91)luc were incubated for 5 days with DMSO (blue) or increasing concentrations of compounds <b>1</b>, <b>2</b>, <b>3</b>, <b>4</b>, <b>5</b>, and <b>6</b> (1 μM (green), 3 μM (violet), 10 μM (yellow), and 30 μM (red)). Confluency was assessed every 4 h in an IncuCyte instrument. Proliferation kinetics shown are representative for at least 3 independent experiments and represent means of 3 wells treated in parallel (* p<0.05, ** p<0.01, *** p<0.01).</p

Nonspecific activity.

<p>HEK293 cells stably expressing Pdcd4_(mut39–91)luc were incubated for 8 h with TPA [10 nM] in combination with increasing concentrations (0.1–30 μM) of compounds <b>1</b>, <b>2</b>, <b>3</b>, <b>4</b>, <b>5</b>, and <b>6</b>. Luciferase activity is given relative to TPA-treated controls. Data are presented as means ± SEM of at least 3 independent experiments (* p<0.05, ** p<0.01, *** p<0.01).</p

Viability.

<p>HEK293 cells stably expressing Pdcd4_(39–91)luc were incubated for 24 h with DMSO (blue) or increasing concentrations of compounds <b>1</b>, <b>2</b>, <b>3</b>, <b>4</b>, <b>5</b>, and <b>6</b> (3 μM (violet), 10 μM (yellow), and 30 μM (red)). Cell death analysis was performed using Annexin V and 7-AAD co-staining. Data are presented as means ± SEM of at least 3 independent experiments (* p<0.05, ** p<0.01, *** p<0.01).</p

6‑(1-Benzyl‑1<i>H</i>‑pyrrol-2-yl)-2,4-dioxo-5-hexenoic Acids as Dual Inhibitors of Recombinant HIV‑1 Integrase and Ribonuclease H, Synthesized by a Parallel Synthesis Approach

The increasing efficiency of HAART has helped to transform HIV/AIDS into a chronic disease. Still, resistance and drug–drug interactions warrant the development of new anti-HIV agents. We previously discovered hit <b>6</b>, active against HIV-1 replication and targeting RNase H in vitro. Because of its diketo-acid moiety, we speculated that this chemotype could serve to develop dual inhibitors of both RNase H and integrase. Here, we describe a new series of 1-benzyl-pyrrolyl diketohexenoic derivatives, <b>7a</b>–<b>y</b> and <b>8a</b>–<b>y</b>, synthesized following a parallel solution-phase approach. Those 50 analogues have been tested on recombinant enzymes (RNase H and integrase) and in cell-based assays. Approximately half (22) exibited inhibition of HIV replication. Compounds <b>7b</b>, <b>7u</b>, and <b>8g</b> were the most active against the RNase H activity of reverse-transcriptase, with IC₅₀ values of 3, 3, and 2.5 μM, respectively. Compound <b>8g</b> was also the most potent integrase inhibitor with an IC₅₀ value of 26 nM

Design, Synthesis, and Structure–Activity Relationship of <i>N</i>‑Arylnaphthylamine Derivatives as Amyloid Aggregation Inhibitors

Dyes like CR are able to inhibit the aggregation of Aβ fibrils. Thus, a screening of a series of dyes including ABBB (<b>1</b>) was performed. Its main component <b>2</b> tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners <b>4</b>–<b>9</b> have been designed and synthesized as inhibitors of Aβ aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC₅₀ of 1–57.4 μM. The most potent compound of this series, <b>4k</b>, showed micromolar activity in this test. Another potent derivative <b>4q</b> (IC₅₀ = 5.6 μM) rapidly crossed the blood–brain barrier, achieving whole brain concentrations higher than in plasma. So <b>4q</b> could be developed to find novel potent antiaggregating βA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates