Quinoxalines against Leishmania amazonensis: SAR study, proposition of a new derivative, QSAR prediction, synthesis, and biological evaluation.

Neglected tropical diseases, such as leishmaniasis, lead to serious limitations to the affected societies. In this work, a structure-activity relationship (SAR) study was developed with a series of quinoxaline derivatives, active against the promastigote forms of Leishmania amazonensis. As a result, a new quinoxaline derivative was designed and synthesized. In addition, a quantitative structure-activity relationship (QSAR) model was obtained [pIC50 = - 1.51 - 0.96 (EHOMO) + 0.02 (PSA); N = 17, R2 = 0.980, R2Adj = 0.977, s = 0.103, and LOO-cv-R2 (Q2) = 0.971]. The activity of the new synthesized compound was estimated (pIC50 = 5.88) and compared with the experimental result (pIC50 = 5.70), which allowed to evaluate the good predictive capacity of the model.

Investigation of dual anti-HIV/HSV activity of oxoquinoline-acylhydrazone derivatives by molecular docking

Abstract Someoxoquinoline-acylhydrazonederivativesshowedactivityagainst HumanImmunodeficiency Virus type 1 (HIV-1). These compounds must also be active against Herpes Simplex Virus type 1 (HSV-1) by an inhibition mechanism where they interact with the HSV-DNA-polymerase/DNA-duplex complex. There are several treatment options for HSV-1 but there is no cure for the disease, which may represent a life risk for individuals co-infected with HIV. In this work molecular docking studies were carried out in an attempt to understand the dual activity of these oxoquinoline-acyhydrazone derivatives. The compounds were docked in two possible situations: (i) in the polymerase domain of HIV-1 Reverse Transcriptase (RT) enzyme in order to verify whether the inhibition occurs similarly to the proposed mechanism for HSV-1 inhibition, where the ligand would form a complex with the enzyme and the DNA; (ii) in the allosteric site of RT in order to verify if the inhibition occur in a similar way to non-nucleoside RT inhibitors (NNRTI). The studied compounds showed higher binding affinity to the allosteric site of RT and the results indicate that the inhibition should occur in a mechanism similar to that of NNRTI, which produces an allosteric inhibition that induces structural changes in the enzymatic active site.

Synthesis and biological evaluation of novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases as potential anticancer agents.

With the aim of discovering new anticancer agents, we have designed and synthesized novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases. The synthesis started with the selective nitration at 5-position of 6-hydroxybenzo[d][1,3]oxathiol-2-one (1) leading to the nitro derivative 2. The nitro group of 2 was reduced to give the amino intermediate 3. Schiff bases 4a-r were obtained from coupling reactions between 3 and various benzaldehydes and heteroaromatic aldehydes. All the new compounds were fully identified and characterized by NMR (1H and 13C) and specifically for 4q by X-ray crystallography. The in vitro cytotoxicity of the compounds was evaluated against cancer cell lines (ACP-03, SKMEL-19 and HCT-116) by using MTT assay. Schiff bases 4b and 4o exhibited promising cytotoxicity against ACP-03 and SKMEL-19, respectively, with IC50 values lower than 5 µM. This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against cancer.

Synthesis and anticancer activity of (E)-2-benzothiazole hydrazones.

Benzothiazole hydrazones have been synthesized and evaluated for their in vitro antiproliferative activity against three human cancer cell lines: HL-60 (leukemia), MDAMB-435 (breast) and HCT-8 (colon). The good cytotoxicity for the three cancer cell lines and theoretical profile of compounds 3o and 3p pointed them as promising lead molecules for anticancer drug design.

The conformational plasticity of calmodulin upon calcium complexation gives a model of its interaction with the oedema factor of Bacillus anthracis.

We analyzed the conformational plasticity of calmodulin (CaM) when it is bound to the oedema factor (EF) of Bacillus anthracis and its response to calcium complexation with molecular dynamics (MD) simulations. The EF-CaM complex was simulated during 15 ns for three different levels of calcium bound to CaM. They were respectively no calcium ion (EF-(Apo-CaM)), two calcium ions bound to the C-terminal domain of CaM (EF-(2Ca-CaM)), and four calcium ions bound to CaM (EF-(4Ca-CaM)). Calculations were performed using AMBER package. The analysis of the MD simulations illustrates how CaM forces EF in an open conformation to form the adenylyl cyclase enzymatic site, especially with the two calcium form of CaM, best suited to fit the open conformation of EF. By contrast, CaM encounters bending and unwinding of its flexible interlinker in EF-(Apo-CaM) and EF-(4Ca-CaM). Calcium binding to one domain of CaM affects the other one, showing a transmission of information along the protein structure. The analysis of the CaM domains conformation along the simulations brings an atomistic and dynamic explanation for the instability of these complexes. Indeed the EF-hand helices of the N-terminal domain tend to open upon calcium binding (EF-(4Ca-CaM)), although the domain is locked by EF. By contrast, the C-terminal domain is strongly locked in the open conformation by EF, and the removal of calcium induces a collapse of EF catalytic site (EF-(Apo-CaM)).