Here, we present an investigation into the structure-activity relationship of the Declining artesunate-mefloquine efficacy against falciparum malaria on the. Mefloquine is a chiral molecule with two asymmetric carbon centres, which means it has four different. Design, synthesis, and pharmacological evaluation of mefloquine-based ligands as novel antituberculosis agents. Synthesis and antituberculosis activity of novel mefloquine-isoxazole carboxylic esters as prodrugs. From serendipity to rational antituberculosis drug discovery of.
Water 30 mL was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was extracted using an aqueous sodium bicarbonate, rinsed with water, and dried with anhydrous Na2SO4. The solvent was removed, and the residue was fractionated in a silica gel column chromatography.
The reaction mixture was kept under stirring at room temperature for 30 min, after which time epichlorohydrin 30 mmol was added to the mixture, which was kept under stirring and reflux for 3 h, when TLC showed the consumption of lawsone. Ethyl acetate 50 mL was added to the reaction mixture, followed by the extraction with a solution of NaCl. The organic layer was dried with anhydrous Na2SO4. The solvent was removed, and the residue was purified by silica gel column chromatography.
Synthesis of naphthoquinones 9 and 10a—c and their yields. ANQS 10a—c An appropriated amine 0.
The reaction solution was kept under stirring and reflux for 3 h, when TLC showed the consumption of starting materials. Ethyl acetate 20 mL was then added to the mixture, followed by extraction with HCl 2N. The water layer was neutralized with NaOH 2N and extracted with ethyl acetate. The solvent was removed and the residue was chromatographed through a silica gel column chromatography.
In Vitro Antiplasmodial Activity There are several in vitro methods commonly used for the assessment of parasite growth inhibition [ 38 ]. The experiment was performed three times, each one in triplicate. The results were evaluated by the Microcal Origin 8. The IC50 was determined by comparison with controls for standard drug and without drugs. The compounds to be tested were diluted in DMSO final concentration of 0.
The culture plates were read by a spectrophotometer with a nm [ 42 ]. The coordinates of the grid box were centered on crystallographic ligands, The protonation states and the tautomers, when possible, were adjusted according to pH 7.
The AutoDock Vina methodology was evaluated by redocking, and its exhaustiveness parameter was set to 24 to achieve more accurate results [ 57 ]. The figures were generated by academic versions of the Discovery Studio 4. Results and Discussion 3.
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Synthesis Three series of naphthoquinones—HNQs, ortho- and para-FNQs—were synthesized, affording 24 compounds, 20 of which had been previously described [ 202934 ], while the other 4 compounds 6h, 7g, 7h, and 8h represent new chemical entities Scheme 1.
When the reaction mixtures were diluted with HCl 2N for 15 min, ortho-FNQs kinetic products were the major products, while when concentrated HCl 12N was used with 3 h of reaction, para-FNQs thermodynamic products were obtained [ 60 ].
In presence of concentrated sulfuric acid, ortho-FNQs can be converted into para-FNQs, a process called isomerization, previously described by Hooker in [ 59 ]; however, this method was not used in the present work. Some of the HNQs, ortho- and para-FNQs described in this work, had also been synthesized by our research group in prior studies, but these were only evaluated against Toxoplasma gondii [ 30 — 32 ].
Journal of Tropical Medicine
All compounds of this series represent new chemical entities. Spectra for the new chemical entities are shown in the Supplementary Data in Supplementary Material available online at https: It is important to highlight that the in vitro assays were performed in 48 h, because that is the duration of the asexual erythrocytic stage of P.
Another interesting aspect to be noted is related to compound pairs with a phenyl and a chlorophenyl substituent in each of these three structural series. The presence of a chlorine atom was planned by analogy with atovaquone, and a surprising result was observed. For the HNQs 6g and 6h and the ortho-FNQs 7g and 7h, the chlorinated derivatives were about three times more active in HNQs and two times more active in ortho-FNQs, while for the para-FNQs series, 8g and 8h, an inverse effect was observed, which could, possibly, be related to the low solubility of these compounds in the conditions of the biological assays.
As expected, ortho-FNQs were more cytotoxic because they can be easier reduced and, therefore, more reactive oxygen species ROS are generated, increasing thus cell damage [ 61 ]. Compounds 8c and 8f are highlighted here because they exhibit the best IC50 values 8c Despite disclosing a moderate activity, compound 8a IC50 The in vitro antiplasmodial activity of some naphthoquinones described in this work was previously described [ 2728 ] as causing completely growth inhibition of an unidentified strain of P.
Recently, Duran-Lengua et al. With respect to the IC50 values, it should be taken into account that, in the present case, the higher IC50 values might be explained by the fact that the in vitro assays were performed upon P.
The methodology was evaluated by redocking, which consists of the docking of crystallographic structures onto the targets binding sites. This simulation can show if the docking parameters and the methodology are adequately adjusted to the system. These results were below the threshold value of 2. These values are relevant in the interpretation of docking results for the HNQs and FNQs, as active compounds are expected to disclose binding energies close to the models atovaquone and DMS and should promote good activities.
In addition, the molecular recognition for compound 8f is improved by two weak noncovalent intermolecular interactions: His47 and the furan oxygen with a distance of 2.
Mefloquine - Wikipedia
These intermolecular interactions might certainly contribute for the biological activity of compounds 6h and 8f. Previous studies have shown the inhibition of Pfcyt bc1 and PfDHOD by naphthoquinones [ 81011 ], and the molecular docking results described here are in accordance with this mode of action, although further enzymatic assays are necessary for confirmation. The insertion of a furan ring in the naphthoquinone moiety increased the biological activity, and the FNQs were, in general, more active than the HNQs.
The ortho-FNQs might be highlighted for their potential antitumoral rather than antiplasmodial effect. However, the following naphthoquinones 6h, 8c, 8d, 8f, and 8g deserve also further investigations.
This study points out to arylnaphthoquinones as new potential inhibitors of the Pfcyt bc1 and PfDHOD enzymes since, for both of these targets, favorable binding energies were calculated. However enzymatic assays are necessary for confirming this hypothesis. Based upon these results, a only nitrogen-based moieties were further explored at the 4-posi- Cytotoxicity: In regards to nitrogen functionalization, the data suggests that the nature of the 4-position amine and the degree of electron den- sity around the nitrogen are most strongly associated with activity.
All phenyl amines tested were nearly devoid of activity, and the Antimalarial and selectivity data for a subset of compounds addition of electron-withdrawing groups further decreased with aromatic side chains are presented in Table 2. The data sug- potency. For example, IC90 values for many of them are similar across the four drug-resis- tant strains with WR and WR in particular illustrat- ing this reduction in cross-susceptibility to related drugs Table 3.
Table 1 This is encouraging, since in vitro susceptibility of clinical isolates P. Consequently, efforts are underway to synthesize more metabolically stable compounds, since their cross-susceptibility profiles are of great interest. In general, these compounds were more potent than MQ and der of magnitude. Thioether WR, ether WR, and displayed a one-log increase in selectivity.
The primary amine benzyl amine WR were more potent and demonstrated a WR is nearly devoid of activity, while the addition of superior selectivity index compared to mefloquine. In this series, methyl, ethyl, propyl, and butyl groups substantially increases effi- the ethers, thioethers, and secondary amines proved most promis- cacy Table 4.
Interestingly, branched alkyl substituents such as i- ing, and second generation libraries based on these lead com- Pr and i-Bu prove quite active, while t-Bu displays moderate activ- pounds are currently being constructed. Chain length also appears to affect activity since n-Bu After constructing a small series of cyclic diamines, we observed WR and n-hexyl WR derivatives have different promising activity emerging within the series as illustrated by levels of potency, presumably resulting from the addition of the WR and WR, which correlate with WR two methylene units.
Likewise, a second generation library based upon cyclic and t-Bu WR derivatives all displayed favorable metabolic motifs is underway.
Mefloquine - Wikipedia
The bidi- chains with additional heteroatoms were also constructed Table rectional permeability of most of the compounds was measured 5. In this series, it became apparent that efficacy is reduced by across MDR1-transformed MDCK cell monolayers in the presence the addition of an alcohol or fluorine within the side chain.
In par- of the PgP inhibitor cyclosporin A. This assay is normally used as ticular, when the hydroxyl group of WR is transformed into an indicator for permeability properties across the blood—brain the methyl ether WRpotency increases by nearly an or- barrier. Structure—activity relationships were studied amongst a library of 4-position analogs of mefloquine. The 4-position alcohol and at least one diamine met the minimum requirement for equivalent potency to mefloquine.
Taken together, these observations suggest a hypothesis for fur- b In vitro IC90 values against four different strains of P.
Second-generation libraries that test this hypothesis are currently underway. Due to the breadth of this library, the compounds were synthesized as racemates.
We are Table 6 currently optimizing a cost-effective, enantiopure synthetic route P. The active lead compounds will be tested in vitro and in vivo as pure enantiomers or diastereomers, respectfully.