Novel Organic Salts Based on Mefloquine: Synthesis, Solubility, Permeability, and In Vitro Activity against Mycobacterium tuberculosis.

The development of novel pharmaceutical tools to efficiently tackle tuberculosis is the order of the day due to the rapid development of resistant strains of Mycobacterium tuberculosis. Herein, we report novel potential formulations of a repurposed drug, the antimalarial mefloquine (MFL), which was combined with organic anions as chemical adjuvants. Eight mefloquine organic salts were obtained by ion metathesis reaction between mefloquine hydrochloride ([MFLH][Cl]) and several organic acid sodium salts in high yields. One of the salts, mefloquine mesylate ([MFLH][MsO]), presented increased water solubility in comparison with [MFLH][Cl]. Moreover, all salts with the exception of mefloquine docusate ([MFLH][AOT]) showed improved permeability and diffusion through synthetic membranes. Finally, in vitro activity studies against Mycobacterium tuberculosis revealed that these ionic formulations exhibited up to 1.5-times lower MIC values when compared with [MFLH][Cl], particularly mefloquine camphorsulfonates ([MFLH][(1R)-CSA], [MFLH][(1S)-CSA]) and mefloquine HEPES ([MFLH][HEPES]).

Anti-tuberculosis evaluation and conformational study of N-acylhydrazones containing the thiophene nucleus.

A series of N-acylhydrazonyl-thienyl derivatives (compounds 2 and 3), mainly of the type 2-(aryl-CH=N-NHCOCH2 )-thiene (2: aryl = substituted-phenyl; 3: aryl = heteroaryl) were evaluated against Mycobacterium tuberculosis. Particularly active compound was 3 (heteroaryl = 5-nitrothien-2-yl or 5-nitrofuran-2-yl) with MIC values of 8.5 and 9.0 µM, respectively. Moderately active compounds were compound 3 (heteroaryl = pyridin-2-yl) and compound 2 containing aryl = 2- or 4-hydroxyphenyl groups, with MIC values between 170 and 408 µM. Compound 2 containing OMe, H, F, Cl, Br, CN, and NO2 substituents and compound 3 (heteroaryl = furan-2-yl, thien-2-yl, pyrrol-2-yl, imidazol-2-yl, pyridin-3-yl, and pyridin-4-yl) were all inactive. Clearly, there is no correlation of activity with the electronic effects of the substituents. The activities suggest different modes of biological action of the compounds having nitro-heteroaryl groups, on the one hand, and the 2-hydroxyphenyl or pyridin-2-yl substituents, on the other hand. Compounds having 2- or 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, or 4-hydroxy-3-chlorophenyl were less cytotoxic than ethambutol. It is important to notice that compound 3 (aryl = 5-NO2 -furan-2-yl) exhibited a promising therapeutic index (TI = 1093.90), with a value 4.4 less than that of ethambutol. Compounds 2 and 3 exist in DMSO or MeOD solutions as mixtures of EC(O)N /EC=N and ZC(O)N /EC=N conformers.

Computational Strategies Targeting Inhibition of Helicobacter pylori and Cryptococcus neoformans Ureases.

Helicobacter pylori and Cryptococcus ssp. are pathogenic ureolytic microorganisms that cause several disorders in the host organism and, in severe cases, lead to death. Both infections have the urease enzyme as a key virulence factor since they use its ability to produce ammonia to soften the inhospitable pH to which they are subjected. In this review, we describe two ureases as possible molecular targets for drug discovery and provide insights for developing potent inhibitors against ureases from these pathogenic microorganisms through computer-aided drug discovery approaches, such as structure-based drug design (SBDD) and structure-activity relationship (SAR). The SAR studies have indicated several essential subunits and groups to be present in urease inhibitors that are critical for inhibitory activity against H. pylori or Cryptococcus spp. Since the threedimensional structure of C. neoformans urease has yet to be determined experimentally, the plant urease of Canavalia ensiformis was used in this study due to its structural similarity. Therefore, in the SBDD context, FTMap and FTSite analyses were performed to reveal characteristics of the urease active sites in two protein data bank files (4H9M, Canavalia ensiformis, and 6ZJA, H. pylori). Finally, a docking-based analysis was performed to explore the best inhibitors described in the literature to understand the role of the ligand interactions with the key residues in complex ligand-urease stabilization, which can be applied in the design of novel bioactive compounds.

In-vitro biological evaluation of 3,3',5,5'-tetramethoxy-biphenyl-4,4'-diol and molecular docking studies on trypanothione reductase and Gp63 from Leishmania amazonensis demonstrated anti-leishmania potential.

Available treatments for leishmaniasis have been widely used since the 1940s but come at a high cost, variable efficacy, high toxicity, and adverse side-effects. 3,3',5,5'-Tetramethoxy-biphenyl-4,4'-diol (TMBP) was synthesized through laccase-catalysis of 2,6-dimethoxyphenol and displayed antioxidant and anticancer activity, and is considered a potential drug candidate. Thus, this study aimed to evaluate the anti-leishmanial effect of TMBP against promastigote and amastigote forms of Leishmania (L.) amazonensis and investigated the mechanisms involved in parasite death. TMBP treatment inhibited the proliferation (IC50 0.62-0.86 µM) and induced the death of promastigote forms by generating reactive oxygen species and mitochondrial dysfunction. In intracellular amastigotes, TMBP reduced the percentage of infected macrophages, being 62.7 times more selective to the parasite (CC50 53.93 µM). TMBP did not hemolyze sheep erythrocytes; indicative of low cytotoxicity. Additionally, molecular docking analysis on two enzyme targets of L. amazonensis: trypanothione reductase (TR) and leishmanolysin (Gp63), suggested that the hydroxyl group could be a pharmacophoric group due to its binding affinity by hydrogen bonds with residues at the active site of both enzymes. TMBP was more selective to the Gp63 target than TR. This is the first report that TMBP is a promising compound to act as an anti-leishmanial agent.

Promising Molecular Targets Related to Polyamine Biosynthesis in Drug Discovery against Leishmaniasis.

Leishmaniasis is a neglected tropical disease widely distributed worldwide, caused by parasitic protozoa of the genus Leishmania. Despite representing a significant public health problem, the therapeutic options are old, with several reported adverse effects, have high costs, with administration mainly by parenteral route, which makes treatment difficult, increasing dropout and, consequently, the emergence of resistant strains. Thus, the research and development of new antileishmanial therapies become necessary. In this field, inhibiting essential targets that affect the parasite's growth, survival, and infectivity represents an attractive therapeutic strategy. With this in mind, this review addresses the main structural, functional characteristics and recent reports of the discovery of promising inhibitors of the enzymes Arginase (ARG) and trypanothione synthase (TryS), which are involved in the biosynthesis of polyamines and trypanothione and Trypanothione Reductase (TR), responsible for the reduction of trypanothione thiol.

In vitro evaluation of antitrypanosomal activity and molecular docking of benzoylthioureas.

A series of sixteen benzoylthioureas derivatives were initially evaluated in vitro against the epimastigote form of Trypanosoma cruzi. All of the tested compounds inhibited the growth of this form of the parasite, and due to the promising anti-epimastigote activity from three of these compounds, they were also assayed against the trypomastigote and amastigote forms. ADMET-Tox in silico predictions and molecular docking studies with two main enzymatic targets (cruzain and CYP-51) were performed for the three compounds with the highest activity. The docking studies showed that these compounds can interact with the active site of cruzain by hydrogen bonds and can be coordinated with Fe-heme through the carbonyl oxygen atom of the CYP51. These findings can be considered an important starting point for the proposal of the benzoylthioureas as potent, selective, and multi-target antitrypanosomal agents.

Benzoylthioureas: Design, Synthesis and Antimycobacterial Evaluation.

BACKGROUND: New drugs and strategies to treat tuberculosis (TB) are urgently needed. In this context, thiourea derivatives have a wide range of biological activities, including anti-TB. This fact can be illustrated with the structure of isoxyl, an old anti-TB drug, which has a thiourea as a pharmacophore group. OBJECTIVE: The aim of this study is to describe the synthesis and the antimycobacterial activity of fifty-nine benzoylthioureas derivatives. METHODS: Benzoylthiourea derivatives have been synthesized and evaluated for their activity against Mycobacterium tuberculosis using the MABA assay. After that, a structure-activity relationship study of this series of compounds has been performed. RESULTS AND DISCUSSION: Nineteen compounds exhibited antimycobacterial activity between 423.1 and 9.6 µM. In general, we observed that the presence of bromine, chlorine and t-Bu group at the para-position in benzene ring plays an important role in the antitubercular activity of Series A. These substituents were fixed at this position in benzene ring and other groups such as Cl, Br, NO2 and OMe were introduced in the benzoyl ring, leading to the derivatives of Series B. In general, Series B was less cytotoxic than Series A, which indicates that the presence of a substituent at benzoyl ring contributes to an improvement in both antimycobacterial activity and toxicity profiles. CONCLUSION: Compound 4c could be considered a good prototype to be submitted to further structural modifications in the search for new anti-TB drugs, since it is 1.8 times more active than the first line anti-TB drug ethambutol and 0.65 times less active than isoxyl.

Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure-Activity Relationship (HQSAR) Modeling of Amino-Imino Tautomers.

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity.

7-Chloro-4-quinolinyl hydrazones: a promising and potent class of antileishmanial compounds.

In this work, we report the antileishmanial evaluation of twenty 7-chloro-4-quinolinyl hydrazone derivatives (1-20). Firstly, the compounds were tested against promastigotes of four different Leishmania species. After that, all derivatives were assayed against L. braziliensis amastigotes and murine macrophages. Furthermore, it was investigated whether the antiamastigote L. braziliensis effect of the compounds could be associated with nitric oxide production. Compounds 6 and 7 showed a strong leishmanicidal activity against intracellular parasite with IC50 in nanogram levels (30 and 20 ng/mL, respectively). Appreciable activity of three compounds tested can be considered an important finding for the rational design of new leads for antileishmanial compounds.

In vitro anti-mycobacterial activity of (E)-N'-(monosubstituted-benzylidene) isonicotinohydrazide derivatives against isoniazid-resistant strains.

A series of twenty-three N-acylhydrazones derived from isoniazid (INH 1-23) have been evaluated for their in vitro antibacterial activity against INH- susceptible strain of M. tuberculosis (RG500) and three INH-resistant clinical isolates (RG102, RG103 and RG113). In general, derivatives 4, 14, 15 and 16 (MIC=1.92, 1.96, 1.96 and 1.86 µM, respectively) showed relevant activities against RG500 strain, while the derivative 13 (MIC=0.98 µM) was more active than INH (MIC=1.14 µM). However, these derivatives were inactive against RGH102, which displays a mutation in the coding region of inhA. These results suggest that the activities of these compounds depend on the inhibition of this enzyme. However, the possibility of other mechanisms of action cannot be excluded, since compounds 2, 4, 6, 7, 12-17, 19, 21 and 23 showed good activities against katG-resistant strain RGH103, being more than 10-fold more active than INH.