Optimization of rifampicin encapsulation in PLGA polymeric reservoirs.

Rifampicin is one of the most commonly used antibiotics for treating tuberculosis, but shows low bioavailability and requires long-term administration, and hence its use may result in severe side effects. Encapsulation of rifampicin in polymeric reservoirs allows it to be administered locally and improves its pharmacological action. High rifampicin loading is crucial for obtaining an adequate therapeutic effect. Generally, the drug loading is a complex function of reservoir fabrication parameters. In the current work, we systematically varied the drug (rifampicin), polymer (PLGA) and dispersed phase contents as well as the solvent evaporation rate, particle size and number of particle washing cycles to characterize the challenges involved in encapsulating rifampicin. Physical insight into the low encapsulation efficiencies was provided, as well as an optimization of fabrication conditions to achieve higher drug loading levels. The particle solidification stage was found in the current work to be the most crucial step, where a significant amount of rifampicin was lost enhanced by its solubility in the aqueous medium. Increases in polymer concentration, solvent evaporation rate and particle size each significantly improved the drug loading by hindering of solvent-assisted escape of the drug. Based on our observation of the drug loading being extremely sensitive to the particle recovery and washing procedure after the solvent evaporation, most of the encapsulated rifampicin was concluded to be located on or very near the reservoir surface. Encapsulation could be significantly improved by fabricating multiple emulsions, especially double w/o/w emulsions, but the resultant particles were relatively large and porous, which might be a drawback for drug administration.

(2Z)-3-Hydroxy-3-(4-R-Phenyl)-Prop-2-Enedithioic Acids as New Antituberculosis Compounds.

BACKGROUND: Tuberculosis is an infectious disease caused by the bacillus Mycobacterium tuberculosis. Compounds including a sulfur-containing scaffold have been shown to be key scaffolds in various antituberculosis agents. Interestingly, the 3-hydroxy-3-phenyl-prop-2-enedithioic acids 11a-j have, to the best of our knowledge, not been previously described as antituberculosis agents. PURPOSE: In the present study, we investigated the role of substituents attached to the phenyl ring of a 3-hydroxy-3-phenyl-prop-2-enedithioic acid scaffold (compounds 11a-j) in inhibiting the growth of M. tuberculosis strain H37Rv. METHODS: (Z)-3-hydroxy-3-(4-R-phenyl)-prop-2-enedithioic acids 11b-j, with R groups including various electron-donating or electron-withdrawing groups, were designed by structurally modifying the lead compound 11a. The syntheses of 11a-j involved each one-step procedure starting from the corresponding substituted acetophenone. Compounds 11a-j were tested against M. tuberculosis strain H37Rv to evaluate their bacterial growth inhibitory activities. ADMET profiles were predicted by employing three different methods. In addition, molecular docking studies were carried out, based on the molecular similarities of the synthesized compounds with ethionamide (5), on the active site of the M. tuberculosis H37Rv (3R)-hydroxyacyl-ACP (HadAB) dehydratase heterodimer. RESULTS: The antituberculosis activities of compounds 11a-j could be explained in terms of the presence of electron-donating or electron-withdrawing substituents on the aromatic ring of the substituted 3-hydroxy-3-phenyl)-prop-2-enedithioic acid core. The activity and selectivity index (SI) value of (Z)-3-hydroxy-3-(4-nitrophenyl)-prop-2-enedithioic acid 11e suggested that this compound could be used for the design of novel antituberculosis agents. Most of the synthesized molecules showed an acceptable ADME profile and a low probability of being toxic. Docking studies of 11d and 11e showed them forming hydrogen bonds with the ACys61 residue of the HadAB enzyme. CONCLUSION: Our results suggested that the antituberculosis compound 11e could be used for the design of novel antituberculosis agents.

Total syntheses and antiproliferative activities of prenostodione and its analogues.

A high-yielding total synthesis of the indole alkaloid prenostodione was completed in 4 steps and 44% overall yield from 1H-indole-3-carboxylic acid. The expedient syntheses of prenostodiones containing distinct substituents at the para position of the phenyl frame underscored the scope of this methodology. The cytotoxic activities of the tert-butyl esters of prenostodione analogues were tested using six tumor cell lines. Preliminary structure-activity studies revealed the importance of the identity of the aromatic substituent at the C-4 position for cytotoxic activity. The IC50 values of these compounds were found to compare satisfactorily with those of the commercially available drugs etoposide and cisplatin. Furthermore, the compounds with, respectively, -OMe (14d) and -NO2 (14f) groups at C-4 were more selective than these control compounds in PC-3, K-562, and MCF-7 cells. Also, computational studies were carried out to determine the ADMET profiles and passive membrane permeabilities of the compounds. The results suggested the promise of 14d and 14f as hit compounds for the development of new anticancer agents.

Synthesis and antituberculosis activity of new acylthiosemicarbazides designed by structural modification.

Acylthiosemicarbazides 8a-n were designed by structural modification of lead Compound 7. The syntheses of 8a-n involve a five-step procedure starting from carboxylic acids. Compounds 8a-n were tested against three Mycobacterium tuberculosis strains to measure their inhibitory antituberculosis activities. These activities could be explained according to the presence or absence of the chlorine substituent in the aromatic ring of the amide joined to the thiosemicarbazide core. Thiosemicarbazide derivative 8n is a candidate for the development of novel antitubercular agents. Ongoing studies are focused on exploring the mechanism by which these compounds inhibit M. tuberculosis cell growth.

5,6-Dihydropyrrolo[2,1-a]isoquinolines as Alternative of New Drugs with Cytotoxic Activity.

In this study, the pyrrolo[2,1-a]isoquinolines 4a-n were synthesized in good yields in a three steps synthesis from the corresponding α,ß-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cytotoxic activity as a function of the electronic properties and aromaticity of the substituent at the C-2 position of the pyrroloisoquinoline. Our results reveal that the cytotoxic activity could be explained in terms of the distribution of electronic density across the ring joined to C-2. Also, this study identified 3-hydroxy (4d) and 3-chloro (4j) derivatives with powerful cytotoxic activities. The IC50 values of these compounds were found to be comparable to those of the commercially available Topotecan, Irinotecan, Etoposide, Tamoxifen, and Cisplatin.