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Lipophilicity is a physicochemical property with wide relevance in drug design, computational biology, food, environmental and medicinal chemistry. Lipophilicity is commonly expressed as the partition coefficient for neutral molecules, whereas for molecules with ionizable groups, the distribution coefficient (D) at a given pH is used. The logDpH is usually predicted using a pH correction over the logPN using the pKa of ionizable molecules, while often ignoring the apparent ion pair partitioning ( P IP app ) ${{\rm{(}}P_{{\rm{IP}}}^{{\rm{app}}} )}$ . In this work, we studied the impact of ( P IP app ) ${{\rm{(}}P_{{\rm{IP}}}^{{\rm{app}}} )}$ on the prediction of both the experimental lipophilicity of small molecules and experimental lipophilicity-based applications and metrics such as lipophilic efficiency (LipE), distribution of spiked drugs in milk products, and pH-dependent partition of water contaminants in synthetic passive samples such as silicones. Our findings show that better predictions are obtained by considering the apparent ion pair partitioning. In this context, we developed machine learning algorithms to determine the cases that P I app ${P_{\rm{I}}^{{\rm{app}}} }$ should be considered. The results indicate that small, rigid, and unsaturated molecules with logPN close to zero, which present a significant proportion of ionic species in the aqueous phase, were better modeled using the apparent ion pair partitioning ( P IP app ) ${{\rm{(}}P_{{\rm{IP}}}^{{\rm{app}}} )}$ . Finally, our findings can serve as guidance to the scientific community working in early-stage drug design, food, and environmental chemistry.

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Anthocyanins are naturally occurring bioactive compounds found mainly in fruits, vegetables, and grains. They are usually extracted due to their biological properties and great potential for technological applications. These compounds have characteristic pH-dependent colorations that are natural dyes since they come in different colors. However, they are susceptible to processing conditions, remarkably light, temperature, and oxygen. The acylated anthocyanins showed better stability characteristics, and therefore, an acylation process of these compounds could improve their applications. The enzymatic acylation was effective and showed promising results. The current review provides an overview of the works that performed enzymatic acylation of anthocyanins and studies on the stability, antioxidant activity, and lipophilicity. In general, enzymatically acylated anthocyanins showed better stability to light and temperature than non-acylated compounds. In addition, they were liposoluble, a characteristic that allows their addition to products with lipid matrices. The results showed that these compounds formed by enzymatic acylation have perspectives of application mainly as natural colorants in food products. Therefore, the enzymatic acylation of anthocyanins appears viable to increase the industrial applicability of anthocyanins. There are still some gaps to be filled in process optimization, the reuse of enzymes, and toxicity analysis of the acylated compounds formed.

Assuntos

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Sequestration of chemical defenses from dietary sources is dependent on the availability of compounds in the environment and the mechanism of sequestration. Previous experiments have shown that sequestration efficiency varies among alkaloids in poison frogs, but little is known about the underlying mechanism. The aim of this study was to quantify the extent to which alkaloid sequestration and modification are dependent on alkaloid availability and/or sequestration mechanism. To do this, we administered different doses of histrionicotoxin (HTX) 235A and decahydroquinoline (DHQ) to captive-bred Adelphobates galactonotus and measured alkaloid quantity in muscle, kidney, liver, and feces. HTX 235A and DHQ were detected in all organs, whereas only DHQ was present in trace amounts in feces. For both liver and skin, the quantity of alkaloid accumulated increased at higher doses for both alkaloids. Accumulation efficiency in the skin increased at higher doses for HTX 235A but remained constant for DHQ. In contrast, the efficiency of HTX 235A accumulation in the liver was inversely related to dose and a similar, albeit statistically nonsignificant, pattern was observed for DHQ. We identified and quantified the N-methylation of DHQ in A. galactonotus, which represents a previously unknown example of alkaloid modification in poison frogs. Our study suggests that variation in alkaloid composition among individuals and species can result from differences in sequestration efficiency related to the type and amount of alkaloids available in the environment.

Assuntos

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Despite being a preventable and curable disease, Tuberculosis (TB) is the world's top infectious killer. Development of new drugs is urgently needed. In this work, the synthesis and characterization of new silver(I) complexes, that include N'-[(E)-(pyridine-2-ylmethylene)pyrazine-2-carbohydrazide, HPCPH, as main ligand and substituted aryl-phosphines as auxiliary ligands, is reported. HPCPH was synthesized from pyrazinoic acid, the active metabolite of the first-line antimycobacterial drug pyrazinamide. Complexes [Ag(HPCPH)(PPh3)2]OTf (1), [Ag(HPCPH)((P(p-tolyl)3)2]OTf (2) and [Ag(HPCPH)(P(p-anisyl)3)2]OTf (3) were characterized in solid state and in solution by elemental analysis and FTIR and NMR spectroscopies (OTftriflate). Crystal structures of (1,2) were determined by XRD. The Ag atom is coordinated to azomethine and pyridine nitrogen atoms of HPCPH ligand and to the phosphorous atom of each aryl-phosphine co-ligand. Although HPCPH did not show activity, the Ag(I) compounds demonstrated activity against Mycobacterium tuberculosis (MTB), H37Rv strain, and multi-drug resistant clinical isolates (MDR-TB). Globally, results showed that the compounds are not only effective against the sensitive strain, but are more potent against MDR-TB than antimycobacterial drugs used in therapy. The compounds showed low to moderate selectivity index values (SI) towards the bacteria, using MRC-5 cells (ATCC CCL-171) as mammalian cell model. Interaction with DNA was explored to get insight into the potential mechanism of action against the pathogen. No significant interaction was detected, allowing to discard this biomolecule as a potential molecular target. Compound 1 was identified as a hit compound (MIC90 2.23 µM; SI 4.4) to develop further chemical modifications in the search for new drugs.

Assuntos

RESUMO

Sequestration of chemical defenses from dietary sources is dependent on the availability of compounds in the environment and the mechanism of sequestration. Previous experiments have shown that sequestration efficiency varies among alkaloids in poison frogs, but little is known about the underlying mechanism. The aim of this study was to quantify the extent to which alkaloid sequestration and modification are dependent on alkaloid availability and/or sequestration mechanism. To do this, we administered different doses of histrionicotoxin (HTX) 235A and decahydroquinoline (DHQ) to captive-bred Adelphobates galactonotus and measured alkaloid quantity in muscle, kidney, liver, and feces. HTX 235A and DHQ were detected in all organs, whereas only DHQ was present in trace amounts in feces. For both liver and skin, the quantity of alkaloid accumulated increased at higher doses for both alkaloids. Accumulation efficiency in the skin increased at higher doses for HTX 235A but remained constant for DHQ. In contrast, the efficiency of HTX 235A accumulation in the liver was inversely related to dose and a similar, albeit statistically nonsignificant, pattern was observed for DHQ. We identified and quantified the N-methylation of DHQ in A. galactonotus, which represents a previously unknown example of alkaloid modification in poison frogs. Our study suggests that variation in alkaloid composition among individuals and species can result from differences in sequestration efficiency related to the type and amount of alkaloids available in the environment.

RESUMO

Fluorescent probes are used in drug nanocarrier pre-clinical studies or as active compounds in theranostics and photodynamic therapy. In the biological medium, nanoparticles interact with proteins, which can result in the off-target release of their cargo. The present study used asymmetric flow field-flow fractionation with online multi-angle laser light scattering and fluorescence detection (AF4-MALLS-FLD) to study the release, transfer, and partition of fluorescent dyes from polymeric nanoparticles (NP). NP formulations containing the dyes Rose Bengal, Rhodamine B, DiI, 3-(α-azidoacetyl)coumarin and its polymer conjugate, Nile Red, and IR780 and its polymer conjugate were prepared. NP suspensions were incubated in a medium with serum proteins and then analyzed by AF4. AF4 allowed efficient separation of proteins (< 10 nm) from fluorescently labeled NP (range of 54 - 180 nm in diameters). The AF4 analyses showed that some dyes, such as Rose Bengal, IR780, and Coumarin were transferred to a high extent (68-77%) from NP to proteins. By contrast, for DiI and dye-polymer conjugates, transfer occured to a lower extent. The studies of dye release kinetics showed that the transfer of IR780 from NP to proteins occurs at a high extent (~50%) and rate, while Nile Red was slowly released from the NP over time with reduced association with proteins (~20%). This experiment assesses the stability of fluorescence labeling of nanocarriers and probes the transfer of fluorescent dyes from NP to proteins, which is otherwise not accessible with commonly used techniques of separation, such as dialysis and ultrafiltration/centrifugation employed in drug encapsulation and release studies of nanocarriers. Determining the interaction and transfer of dyes to proteins is of utmost importance in the pre-clinical evaluation of drug nanocarriers for improved correlation between in vitro and in vivo studies.

Assuntos

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This work deals with the theoretical approach of biodegradability, lipophilicity, and physiological activity of VAL and four degradation products (DPs) detected after 20 min of the photo-electro-Fenton (PEF) process. The biodegradability calculation, taking into account the change in the theoretical oxygen demand, showed that the four DPs had a more negative value than VAL, indicating that they are more susceptible to oxidation. However, these results do not imply more accessible biotransformation pathways than VAL, as observed using the EAWAG-BBD program, through which neutral biotransformation pathway prediction for VAL and DPs was made. Subsequently, by calculating the theoretical lipophilicity of the molecules (log P), the theoretical toxicity of the DPs was proposed, where the DPs had log P values between 1 and 3, lower values than those of VAL (log P = 4), indicating that DPs could be less toxic than the original compound (VAL). Both results suggest that VAL degradation (by photo-electro-Fenton process proposed) yields a positive effect on the environment. Finally, when molecular dynamic simulations were carried out, it was observed that DP1, DP2, and DP3 maintained similar interactions to those of VAL with the binding site of the AT1R. DP4 did not show any interaction. These results indicated that, despite the presence of DPs, generated after 20 min of the treatment, they could not exert a physiological activity in any organism the same way that does VAL.

Assuntos

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Cinnamic acids and their derivatives are found in abundance in fruits, vegetables, and other food products of plant origin. The trans-cinnamic and p-coumaric acids in particular have been a subject of research for the treatment of a diverse range of pathological conditions. However, it is unclear whether these derivatives exert a direct beneficial effect on the cells that play a role in regulating skin wound healing, such as fibroblasts. In this study, using in vitro scratch-wound healing assay, it was observed that treatment with trans-cinnamic acid resulted in increased migration of fibroblasts when compared with that of p-coumaric acid-treated cells, without any adverse effect on cell viability. Studies on the lipophilicity of these acids using the XLOGP3 algorithm showed that trans-cinnamic acid was more lipophilic than p-coumaric. Thus, the findings of this study indicated that the lipophilic characteristic of trans-cinnamic acid rendered it more suitable as a potential drug candidate.

Assuntos

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In the present study, seven 2',4'-dihydroxydihydrochalcone derivatives (compounds 3-9) were synthesized and their capacity as anti-Saprolegnia agents were evaluated against Saprolegnia parasitica, S. australis, S. diclina. Derivative 9 showed the best activity against the different strains, with minimum inhibitory concentration (MIC) and minimum oomyceticidal concentration (MOC) values between 100-175 µg/mL and 100-200 µg/mL, respectively, compared with bronopol and fluconazole as positive controls. In addition, compound 9 caused damage and disintegration cell membrane of all Saprolegnia strains over the action of commercial controls.

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A series of1,2,4- and 1,3,4-oxadiazole derivatives were synthesized and evaluated for their anticancer activity. Halogenated 1,2,4-oxadiazoles were obtained from benzonitrile and coupled either lipophilic amines or with aminoalcohols. Lipophilic 1,3,4-oxadiazole derivatives were obtained through the Mannich reactions between 5-(aryl)-1,3,4-oxadiazole-2-thiol and alkylated or acylated amines. The in vitro cytotoxic effects were evaluated against 4T1- mammary carcinoma and CT26 - colon cancer cells. The best results were obtained for the 1,3,4-oxadiazole coupled to alkylated piperazine with 10-14 carbon chain moiety, with IC50 values ranging from 1.6 to 3.55µΜ for the 4T1 cell line, and from 1.6 to 3.9 µM for the CT26.WT cell line, and selectivity index up to 19. The most potent compounds were investigated with AnnexinV and PI staining as indicative of apoptosis induction.

Assuntos