Series of bisquinolines 4–15 and bispyrrolo1,2aquinoxalines 16–20 containing various polyamine linkers were synthesized. The aqueous solubility and distribution coefficient were experimentally ...determined. The compounds were screened for antimalarial activity alongside chloroquine against D10 and Dd2 strains of Plasmodium falciparum. The growth inhibitory effects of biscompounds 4–9 were assessed against various cancer cell lines. The aqueous solubility was found to increase with an increase in potential proton.ation sites. Bisquinolines 8 and 9 featuring triethylenetetramine and N,N′-bis(3-aminopropyl)ethylene-diamine linkers, respectively, were the most active of all synthesized compounds. They were found as potent as chloroquine against D10 but significantly more potent against the Dd2 strain, with good selectivity towards parasitic cells. Compound 4 containing a diethylenetriamine bridge displayed the most important anticancer activity of the series, and was a more effective antiproliferative inhibitor than etoposide against all three TK10, UACC62 and MCF7 cancer cell lines.
Series of bisquinoline and bispyrrolo1,2aquinoxaline compounds were synthesized and their in vitro antimalarial activity as well as cytotoxicity were determined. Display omitted
► Synthesis of a series of bisquinolines and bispyrroloquinoxalines. ► Evaluation of antimalarial activity of series. ► Bisquinolines are more active than bispyrroloquinoxalines. ► Bis(7-chloroquinoline)s are more potent than chloroquine against Dd2 strain.
The aim of this study was to synthesize a series of quinoline–pyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a ...two-step nucleophilic substitution process involving quinoline and pyrimidine moieties. They were screened alongside chloroquine (CQ), pyrimethamine (PM) and fixed combinations thereof against the D10 and Dd2 strains of Plasmodium falciparum. The cytotoxicity was determined against the mammalian Chinese Hamster Ovarian cell line. The compounds were all active against both strains. However, hybrid (21) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain, and possessed a moderately superior potency over CQ against the Dd2 strain (IC50: 0.157 vs 0.417μM, ∼threefold), and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains.
In this study, a series of 11 10-aminoethylether derivatives of artemisinin were synthesised and their antimalarial activity against both the chloroquine sensitive (D10) and resistant (Dd2) strains ...of Plasmodium falciparum was determined. The compounds were prepared by introducing aliphatic, alicyclic and aromatic amine groups with linkers of various chain lengths through an ethyl ether bridge at C-10 of artemisinin using conventional and microwave assisted syntheses, and their structures were confirmed by NMR and HRMS. All derivatives proved to be active against both strains of the parasite. The highest overall activity was displayed by the short chain aromatic derivative 8 (IC50=1.44nM), containing only one nitrogen atom, while long chain polyamine derivatives were found to have the lowest activity against both strains. An interesting correlation between the IC50, pKa values and resistance index (RI) was found.
Objectives The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties ...and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains.
Methods The ethers were synthesized in a one‐step process by coupling ethylene glycol moieties of various chain lengths to carbon C‐10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine‐sensitive (D10) and moderately chloroquine‐resistant (Dd2) strains of P. falciparum.
Key findings The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8, featuring three ethylene oxide units, was the most active of all the synthesized ethers.
Conclusions The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water‐soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water‐soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length.
Objectives The aim of this study was to synthesise and determine the transdermal penetration of cytarabine alkylamide derivatives and assess the correlation of flux with physicochemical properties.
...Methods The alkylamide derivatives of cytarabine were synthesised by acylation at the N4‐amino group by the mixed anhydride method. The in‐vitro permeation studies were performed using the Franz diffusion cell methodology. Furthermore, partition coefficients (n‐octanol–water) and aqueous solubility of the N4‐alkylamide derivatives of cytarabine were determined in order to obtain information about their lipophilicity and hydrophilicity.
Key findings The N4‐alkylamides of cytarabine (acetyl, butanoyl, hexanoyl, octanoyl, and decanoyl derivatives) showed decreased hydrophilicity and increased lipophilicity. The log D values of the alkylamides were higher than that of the parent compound and increased linearly as the alkyl chain lengthened. N4‐hexanoyl‐4‐amino‐1‐(2R,3S,4R,5R)‐3,4‐dihydroxy‐5‐(hydroxymethyl)oxolan‐2‐yl pyrimidin‐2‐one) showed the highest median steady‐state flux (Jss) of 89.0 nmol/cm2 per h in the series, which shows a high statistical difference with the parent compound flux value (3.70 nmol/cm2 per h).
Conclusions The prodrug approach appears to be a promising strategy for the enhancement of transdermal penetration of cytarabine.
The objective of this study was to determine the in vitro transdermal permeation through the human stratum corneum (SC) of the antiretroviral (ARV) drug lamivudine (3TC) (1) and its synthesised ...methoxypoly(ethylene glycol) (MPEG) carbamates and carbonates in phosphate buffer solution and with the use of Pheroid as delivery system and to establish a relationship, if any, with selected physicochemical properties. The synthesis and in vitro human skin permeation flux of three N4-methoxypoly(ethylene glycol) carbamates (3)-(5) and three 6'-O-methoxypoly(ethylene glycol) carbonates (6)-(8) of lamivudine are reported. The derivatives were synthesised in a two-step process by coupling activated MPEG oligomers of various chain lengths to either the 4-amino or 6'-hydroxy group of lamivudine. Irrespective of the oligomeric series of derivatives (carbamate or carbonate), the aqueous solubility increases as the MPEG chain lengthens while the solubility in octanol (lipophilicity) remained almost constant. Regardless of the mechanism of diffusion viz. passive (in PBS) or use of enhancer (Pheroid), no derivative penetrate the skin better than the parent drug itself. The use of Pheroid even appeared to significantly retard the skin permeation.
Currently, macromolecular drugs such as proteins are mainly administered by means of injections due to their low intestinal epithelial permeability and poor stability in the gastrointestinal tract. ...This study investigated binary combinations of chemical drug absorption enhancers to determine if synergistic drug absorption enhancement effects exist.
Aloe vera
,
Aloe ferox
and
Aloe marlothii
leaf gel materials, as well as with
N
-trimethyl chitosan chloride (TMC), were combined in different ratios and their effects on the transepithelial electrical resistance (TEER), as well as the transport of FITC-dextran across Caco-2 cell monolayers, were measured. The isobole method was applied to determine the type of interaction that exists between the absorption enhancers combinations. The TEER results showed synergism existed for the combinations between
A. vera
and
A. marlothii
,
A. marlothii
and
A. ferox
as well as
A. vera
and TMC. Antagonism interactions also occurred and can probably be explained by chemical reactions between the chemical permeation enhancers, such as complex formation. In terms of FITC-dextran transport, synergism was found for combinations between
A. vera
and
A. marlothii
,
A. marlothii
and
A. ferox
,
A. vera
and TMC,
A. ferox
and TMC and
A. marlothii
and TMC, whereas antagonism was observed for
A. vera
and
A. ferox.
The combinations where synergism was obtained have the potential to be used as effective drug absorption enhancers at lower concentrations compared to the single components.
The purpose of this study was to synthesize and determine the in vitro transdermal penetration of cytarabine and its 5'-alkyl esters and to establish a correlation, if any, with selected ...physicochemical properties. The n-alkyl esters were synthesized by acylation of cytarabine (1) at its pharmacophoric 5'-OH. The transdermal flux values of (1) and its esters were determined in vitro using Franz diffusion cell methodology. Aqueous solubility and log D (pH 7.4) values were determined and assessed for correlation to transdermal flux. An inverse relation was observed between the water solubility (Sw) and log D values. Of all esters, (4) exhibited the highest flux value of 22.2 nmol x cm(-2) x h(-1), which is significantly different to that of the parent drug cytarabine (3.70 nmol x cm(-)2 x h(-1)). No trend was found between water solubility and flux values.
The objective of this study was to synthesize derivatives of the anti-HIV drug stavudine (d4T) with more favourable physicochemical properties for transdermal delivery in an effort to increase ...transdermal penetration of stavudine and thus reduce the severe side effects associated with the dose-dependent oral therapy. The synthesis, hydrolytic stability, and in vitro human skin permeation flux of a series of novel methoxypoly(ethylene glycol) (MPEG) carbonates of stavudine are reported. The carbonates were synthesized in a two-step process by coupling the MPEG promoiety of various chain lengths to C-5' of d4T. In kinetic studies the carbonates proved to be markedly stable in weakly acidic phosphate medium (pH 5.0) with half-lives ranging from 16 to 58 days. The aqueous solubility increased as the ethylene oxide chain lengthened. However, there was no significant increase in the estimated solubility in octanol. In vitro in the phosphate buffer (200 mM; pH 5.0) almost all carbonates permeate the human skin. However, the most effective penetrant, the derivative with 3 ethylene oxide units in the side chain, exhibited a flux of 26.1 nmol/cm(2)/h as compared to 59.15 nmol/cm(2)/h of the parent drug stavudine. Thus, no permeation enhancement was observed during this study.
The aim of this study was to explore the relation between self-regulation, psychopathology and gender amongst a group of South African university students (N=384). Self-regulation was measured with ...the Shortened Self-Regulation Questionnaire (SSRQ: Carey, Neal, & Collins, 2004), and psychopathology with the General Health Questionnaire (GHQ: Goldberg & Hiller, 1979) as well as with an alcohol- and eating risk questionnaire. Results: A negative association was found between self-regulation and psychopathology, but significantly stronger for male students. Self-regulation was found to be more important to males regarding alcohol use and to females regarding eating behaviour. Gender differences in the relationship between self-regulation and psychopathology are probably due to differences in the tendency to rely on self or others, as well as to differences in socio-cultural and control mechanisms regarding alcohol and eating behaviour.
