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1.
SLAS Discov ; 24(7): 755-765, 2019 08.
Article in English | MEDLINE | ID: mdl-31180789

ABSTRACT

The current methodologies used to identify promising new anthelmintic compounds rely on subjective microscopic examination of worm motility or involve genetic modified organisms. We describe a new methodology to detect worm viability that takes advantage of the differential incorporation of the fluorescent molecular marker propidium iodide and the 2,1,3-benzothiadiazole core, which has been widely applied in light technology. The new assay developed could be validated using the "Pathogen Box" library. By use of this bioassay, it was possible to identify three molecules with activity against Caenorhabditis elegans that were previously described as effective in in vitro assays against other pathogens, such as Schistosoma mansoni, Mycobacterium tuberculosis, and Plasmodium falciparum, accelerating the identification of molecules with anthelmintic potential. The current fluorescence-based bioassay may be used for assessing C. elegans viability. The described methodology replaces the subjectivity of previous assays and provides an enabling technology that is useful for rapid in vitro screens of both natural and synthetic compound libraries. It is expected that the results obtained from these robust in vitro screens would select the most effective compounds for follow-up in vivo experimentation with pathogenic helminths.


Subject(s)
Anthelmintics/pharmacology , Caenorhabditis elegans/drug effects , Drug Discovery/methods , Fluorescent Dyes/chemistry , Parasitic Sensitivity Tests/methods , Thiadiazoles/chemistry , Animals , Kinetics , Molecular Structure , Optical Imaging/methods
2.
SLAS Discov, v. 24, n. 7, p. 755-765, jun. 2019
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-2787

ABSTRACT

The current methodologies used to identify promising new anthelmintic compounds rely on subjective microscopic examination of worm motility or involve genetic modified organisms. We describe a new methodology to detect worm viability that takes advantage of the differential incorporation of the fluorescent molecular marker propidium iodide and the 2,1,3-benzothiadiazole core, which has been widely applied in light technology. The new assay developed could be validated using the "Pathogen Box" library. By use of this bioassay, it was possible to identify three molecules with activity against Caenorhabditis elegans that were previously described as effective in in vitro assays against other pathogens, such as Schistosoma mansoni, Mycobacterium tuberculosis, and Plasmodium falciparum, accelerating the identification of molecules with anthelmintic potential. The current fluorescence-based bioassay may be used for assessing C. elegans viability. The described methodology replaces the subjectivity of previous assays and provides an enabling technology that is useful for rapid in vitro screens of both natural and synthetic compound libraries. It is expected that the results obtained from these robust in vitro screens would select the most effective compounds for follow-up in vivo experimentation with pathogenic helminths.

3.
SLAS Discov ; 24(7): p. 755-765, 2019.
Article in English | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: but-ib16081

ABSTRACT

The current methodologies used to identify promising new anthelmintic compounds rely on subjective microscopic examination of worm motility or involve genetic modified organisms. We describe a new methodology to detect worm viability that takes advantage of the differential incorporation of the fluorescent molecular marker propidium iodide and the 2,1,3-benzothiadiazole core, which has been widely applied in light technology. The new assay developed could be validated using the "Pathogen Box" library. By use of this bioassay, it was possible to identify three molecules with activity against Caenorhabditis elegans that were previously described as effective in in vitro assays against other pathogens, such as Schistosoma mansoni, Mycobacterium tuberculosis, and Plasmodium falciparum, accelerating the identification of molecules with anthelmintic potential. The current fluorescence-based bioassay may be used for assessing C. elegans viability. The described methodology replaces the subjectivity of previous assays and provides an enabling technology that is useful for rapid in vitro screens of both natural and synthetic compound libraries. It is expected that the results obtained from these robust in vitro screens would select the most effective compounds for follow-up in vivo experimentation with pathogenic helminths.

4.
ACS Omega ; 3(4): 3874-3881, 2018 Apr 30.
Article in English | MEDLINE | ID: mdl-30023883

ABSTRACT

The current article describes the synthesis, characterization, and application of a designed hybrid fluorescent BTD-coumarin (2,1,3-benzothiadiazole-coumarin) derivative (named BTD-Lip). The use of BTD-Lip for live-cells staining showed excellent results, and lipid droplets (LDs) could be selectively stained. When compared with the commercially available dye (BODIPY) for LD staining, it was noted that the designed hybrid fluorescence was capable of staining a considerable larger number of LDs in both live and fixed cells (ca. 40% more). The new dye was also tested on live Caenorhabditis elegans (complex model) and showed an impressive selectivity inside the worm, whereas the commercial dye showed no selectivity in the complex model.

5.
Molecules ; 21(2)2016 Feb 18.
Article in English | MEDLINE | ID: mdl-26901183

ABSTRACT

Methotrexate (MTX) is an immunosuppressive drug for systemic use in the treatment of skin diseases, however, MTX presents a number of side effects, such as hepatotoxicity. To overcome this limitation, this study developed skin MTX delivery surfactant systems, such as a microemulsion (ME) and a liquid crystalline system (LCS), consisting of a glycol copolymer-based silicone fluid (SFGC) as oil phase, polyether functional siloxane (PFS) as surfactant, and carbomer homopolymer type A (C971) dispersion at 0.5% (wt/wt) as aqueous phase. Polarized light microscopy and small-angle X-ray scattering evidenced the presence of hexagonal and lamellar LCSs, and also a ME. Texture profile and in vitro bioadhesion assays showed that these formulations are suitable for topical application, showing interesting hardness, adhesiveness and compressibility values. Rheology analysis confirmed the Newtonian behaviour of the ME, whereas lamellar and hexagonal LCSs behave as pseudoplastic and dilatant non-Newtonian fluids, respectively. In vitro release profiles indicated that MTX could be released in a controlled manner from all the systems, and the Weibull model showed the highest adjusted coefficient of determination. Finally, the formulations were not cytotoxic to the immortalized human keratinocyte line HaCaT. Therefore, these bioadhesive surfactant systems established with PFS and C971 have great potential as skin delivery systems.


Subject(s)
Methotrexate/pharmacology , Skin/drug effects , Surface-Active Agents/chemistry , Administration, Topical , Animals , Cell Line , Cell Survival/drug effects , Drug Delivery Systems , Humans , Methotrexate/chemistry , Microscopy, Polarization , Rheology , Scattering, Small Angle , Swine
6.
J Med Chem ; 57(7): 3126-39, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24568559

ABSTRACT

We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.


Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Antitubercular Agents/pharmacology , Drug Discovery , Membrane Transport Proteins/metabolism , Mycobacterium tuberculosis/drug effects , Bacteria/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Drug Design , Female , Fungi/drug effects , Humans , MCF-7 Cells , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Models, Molecular , Molecular Structure , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiology , Tumor Cells, Cultured
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