Fluorine Atoms on C6H5-Corrole Affect the Interaction with Mpro and PLpro Proteases of SARS-CoV-2: Molecular Docking and 2D-QSAR Approaches.

The chymotrypsin-like cysteine protease (3CLpro, also known as main protease-Mpro) and papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been used as the main targets for screening potential synthetic inhibitors for posterior in vitro evaluation of the most promising compounds. In this sense, the present work reports for the first time the evaluation of the interaction between Mpro/PLpro with a series of 17 porphyrin analogues-corrole (C1), meso-aryl-corrole (C2), and 15 fluorinated-meso-aryl-corrole derivatives (C3-C17) via molecular docking calculations. The impact of fluorine atoms on meso-aryl-corrole structure was also evaluated in terms of binding affinity and physical-chemical properties by two-dimensional quantitative structure-activity relationship (2D-QSAR). The presence of phenyl moieties increased the binding capacity of corrole for both proteases and depending on the position of fluorine atoms might impact positively or negatively the binding capacity. For Mpro the para-fluorine atoms might decrease drastically the binding capacity, while for PLpro there was a certain increase in the binding affinity of fluorinated-corroles with the increase of fluorine atoms into meso-aryl-corrole structure mainly from tri-fluorinated insertions. The 2D-QSAR models indicated two separated regions of higher and lower affinity for Mpro:C1-C17 based on dual electronic parameters (σI and σR), as well as one model was obtained with a correlation between the docking score value of Mpro:C2-C17 and the corresponding 13C nuclear magnetic resonance (NMR) chemical shifts of the sp2 carbon atoms (δC-1 and δC-2) of C2-C17. Overall, the fluorinated-meso-aryl-corrole derivatives showed favorable in silico parameters as potential synthetic compounds for future in vitro assays on the inhibition of SARS-CoV-2 replication.

Effects of a new antiprotozoal drug, N,N'-diphenyl-4-methoxy-benzamidine, on energy-linked functions of rat liver mitochondria.

Amidines are chemically characterized by the presence of two nitrogen atoms that bind to the same carbon atom in its structure. Several biological activities have been ascribed to these compounds. Pentamidine, an aromatic diamidine, is effective in the treatment against Pneumocystis carinii and leishmaniasis, but it can also have severe side effects. New amidine derivatives have been synthesized, among them N,N'-diphenyl-4-methoxy-benzamidine (methoxyamidine), which is effective against Leishmania amazonensis (LD50 = 20 µM) and Trypanosoma cruzi (LD50 = 59 nM). In the present study, methoxyamidine toxicity was evaluated in isolated rat liver mitochondria at the same range of concentrations that exert antiprotozoal activity. In these organelles, actively oxidizing glutamate + malate inhibited state 3 respiration (25 nmol mg-1 of protein) by ∼15%. The sites of inhibition in the respiratory chain were complex I and the segment between ubiquinone and complex III. Methoxyamidine also stimulated state 4 respiration by ∼32% and ∼43% at 50 and 65 nmol mg-1 of protein, respectively. Its uncoupling effect was confirmed by a dose-dependent increase in oxygen consumption in state 4 respiration that was induced by oligomycin, reaching up to ∼69% (65 nmol mg-1 of protein) and an increase in ATPase activity in intact mitochondria by ∼27% and ∼83% at 50 and 65 nmol mg-1 protein, respectively. Swelling that was supported by the oxidation of glutamate + malate in the presence of sodium acetate was reduced by methoxyamidine by ∼16% and 32% at 50 and 65 nmol mg-1 protein, respectively. Mitochondrial swelling in the absence of substrate and in the presence of K+ and valinomycin was inhibited by ∼20% at the same concentrations, suggesting that methoxyamidine affects mitochondrial membrane permeability and fluidity. Our data show that methoxyamidine has slight effects on the energy-linked functions of isolated mitochondria at concentrations that correspond to the LD50 against Leishmania amazonensis and Trypanosoma cruzi. These findings may prompt further studies that evaluate methoxyamidine toxicity in vivo.

Synthesis and biological evaluation of N-alkyl naphthoimidazoles derived from ß-lapachone against Trypanosoma cruzi bloodstream trypomastigotes.

The QSAR study of 34 2-aryl-naphthoimidazoles screened so far revealed that σi is the most important factor for their lytic activity on the bloodstream trypomastigote forms of T. cruzi, the etiologic agent of Chagas disease. Based on this result, 16 new N-alkyl-naphthoimidazoles derived from 6,6-dimethyl-3,4,5,6-tetrahydrobenzo[7,8]chromene[5,6-d]imidazole (the product of the reaction of ß-lapachone with paraformaldehyde) by its reaction with halo-alkanes were prepared and evaluated against the parasite and peritoneal macrophages. The N1-n-hexyl and N3-n-hexyl naphthoimidazoles were 2.2 and 3.2 times more active than the standard drug benznidazole with selectivity indices of 2.7 and 13.4, respectively.

Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis.

A series of eleven 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones (16-27) was synthesised as part of a study to search for potential new drugs with a leishmanicidal effect. The thiosemicarbazones, ten of which are new compounds, were prepared in good yields (85-98%) by the reaction of 3,4-methylenedioxyde-6-benzaldehydes (6-X-piperonal), previously synthesised for this work by several methodologies, and thiosemicarbazide in ethanol with a few drops of H2SO4. These compounds were evaluated against Leishmania amazonensis promastigotes, and derivatives where X = I (22) and X = CN (23) moieties showed impressive results, having IC50 = 20.74 µM and 16.40 µM, respectively. The intracellular amastigotes assays showed IC50 = 22.00 µM (22) and 17.00 µM (23), and selectivity index >5.7 and >7.4, respectively, with a lower toxicity compared to pentamidine (positive control, SI = 4.5). The results obtained from the preliminary QSAR study indicated the hydrophobicity (log P) as a fundamental parameter for the 2D-QSAR linear model. A molecular docking study demonstrated that both compounds interact with flavin mononucleotide (FMN), important binding site of NO synthase.

Synthesis, antileishmanial activity and structure-activity relationship of 1-N-X-phenyl-3-N'-Y-phenyl-benzamidines.

Two series of N,N'-diphenyl-benzamidines were synthesized as part of a study to search potential new drugs with antileishmanial activity. These compounds were obtained by anilides in PCl5 halogenation reaction with generation in situ of the corresponding benzimidoyl chlorides, and subsequently treatment with adequate anilines. The series I showed expressive results of antileishmanial activity, highlighted the compounds 9a with IC50 = 81.28 µM (log IC50 = 1.91 µM) against Leishmania chagasi, 8e with IC50 = 26.30 (log IC50 = 1.52 µM) against Leishmania braziliensis. From the results obtained from SAR study (series I), the series II was planned from Craig 2-dimensional map, in which was possible the discovery of the potent compounds, 9v and 9j with IC50 = 12.60 µM (log IC50 = 1.10 µM) and 13.00 µM (log IC50 = 1.11 µM), respectively, against Leishmania amazonensis. The results obtained from the SAR and QSAR studies indicated the best results when electron-donor groups in the ring attached to amidinic carbon, unlike when electron-withdrawing groups at the phenyl-N ring showing inhibitory activity increased. Furthermore, the QSAR model obtained indicated the hydrophobicity as a fundamental property for antileishmanial activity presented by these series.