Antileismanial activity, mechanism of action study and molecular docking of 1,4‐bis(substituted benzalhydrazino)phthalazines

Abstract

To identify new agents for the treatment of American cutaneous leishmaniasis, a series of eight 1,4-bis(substituted benzalhydrazino)phthalazines was evaluated against Leishmania braziliensis and Leishmania mexicana parasites. These compounds represent a disubstituted version of the 1-chloro-4-(monoaryl/heteroarylhydranizyl)phthalazine that exhibited a significant response against L. braziliensis according to our previous findings. Two disubstituted phthalazines 3b and 3f were identified as potential antileishmanial agents against L. braziliensis parasites, exhibiting a submicromolar IC 50 response of 2.37 and 7.90 µM on the promastigote form, and of 1.82 and 4.56 µM against intracellular amastigotes, respectively. In particular, compound 3b showed interesting responses against amastigote isolates from reference, glucantime-resistant and clinical human strains, which were by far superior to the biological response found for the glucantime drug. With regard to the toxicity results, both 3b and 3f exhibited moderate LD 50 values against murine macrophages (BMDM), with good selectivity indexes on promastigotes and intracellular amastigotes of L. braziliensis. A comparison of biological response was established between the monosubstituted and disubstituted versions of these benzalhydrazino-phthalazines. Easy synthetic procedure and significant response against amastigote strains including against resistant lines made compound 3b a potential candidate for further pharmacokinetic and in vivo experiments as antileishmanial agent, and as a platform for further structural optimization. Mechanism-of-action studies and molecular docking simulations discarded the inhibition of superoxide dismutase as possible mode of action.

Antimalarial Activity of Highly Coordinative Fused Heterocycles Targeting β-Hematin Crystallization

“…Initially, we focused on the ability of the 66 compounds to inhibit β-hematin crystallization by using the reported method with a few modifications (Tables and ). − All these compounds were previously prepared and characterized by our group. − ,, From the 4-chloro-1-phthalazine-aryl/heteroarylhydrazinyl derivatives, four of them ( 1a , 1d , 1e , and 1h ) displayed moderate inhibitory responses with IC 50 values ranging from 11.34 to 15.93 μM. Phthalazines 1f and 1k exhibited modest inhibitory responses of IC 50 = 28.79 and 28.80 μM, respectively, whereas the rest of phthalazine-hydrazones including those constructed from acetophenone, i.e., 1n – 1t , displayed poor inhibitory responses (IC 50 > 50 μM).…”

“…The toxicity assay was performed for the most prominent inhibitors 1d , 1e , 1h , 2a , 2b , 2d , 2e , 2f , 2h , 3b , 3c , 5a , and 5k by using peritoneal murine macrophages. The latter were obtained from the mouse peritoneal cavity. − Toxicity results (expressed in terms of CC 50 ) are summarized in Table . Among the studied compounds, 1d , 3b , 3c , and 2f exhibited the lowest toxicity against macrophage cells with CC 50 values higher than 100 μM, followed by the N 1 -aryl-benzo­[ b ]­naphthyridin-4­(1 H )­ones 5a and 5k with CC 50 values of 67.54 and 40.53 μM, respectively, the 1,4-disubstituted phthalazines 2a – 2f with CC 50 values from 31.56 to 56.32 μM, and the monosubstituted phthalazines 1e and 1h with CC 50 values of 29.43 and 45.54 μM, respectively.…”

“…(4.5), was chosen for further assays, taking advantage of its potential as a leishmanicidal agent against infective strains of the Leishmania parasite. 30 Within group 3, despite the similar inhibitory or cytotoxicity response found between compounds 3b and 3c, 3c was chosen for further assay based on its recognized antiparasitic activity. Previously, we demonstrated the potential of 3c as a leishmanicidal agent with significant in vitro activity against the infective and resistant strain of the Leishmania parasite, which was higher than that found for derivative 3b.…”

“…All these compounds were previously synthesized and evaluated against in vitro models of Trypanosome cruzi and Leishmania spp. parasites. − These parasites are responsible for Leishmaniasis and Chagas disease, respectively, and they, in conjunction with malaria, belong to the group of neglected tropical diseases . Despite the genetic and host preference differences between the trypanosomatids and the Plasmodium parasites, it is common to find antitrypanosomatid agents with good antimalarial activity. , …”

Reduction of Nitroarenes via Catalytic Transfer Hydrogenation Using Formic Acid as Hydrogen Source: A Comprehensive Review

“…Reduction of nitroarenes to the corresponding amines is one of most important transformation in the organic synthesis with potential application in the industry for the preparation of bioactive compounds, [1–7] fertilizing products, dyes, pigments, additives and polymers [1–3] . Traditionally, the anilines are prepared from Bechamp′s reduction on corresponding nitroarenes using metal (Zn, Fe, or Sn) in presence of a Brønsted acid at elevated temperature [8] .…”