Manar M. Salem

Natural products from plants as drug candidates and lead compounds against leishmaniasis and trypanosomiasis.

Millions of people in the developing world are affected by diseases caused by the kinetoplastid parasites: the leishmaniases, African trypanosomiasis, and Chagas disease. In many cases the drugs employed for treatment are toxic, marginally effective, given by injection, and/or compromised by the development of resistance. Since safe, effective, and affordable chemotherapeutic agents for leishmaniasis and trypanosomiasis are clearly needed, the identification of new antikinetoplastid drug candidates should be an urgent priority. Numerous plant-derived natural products from different structural classes have been investigated as antileishmanial and antitrypanosomal candidates, including various alkaloids, terpenoids, flavonoids, and quinonoids. This review outlines the antikinetoplastid activities of plant-derived natural products reported in the literature and also provides an overview of mechanistic studies that have been conducted with these compounds. Given the activities of these agents and their diverse range of effects on parasite biology, natural products are a potentially rich source of drug candidates and leads against leishmaniasis and trypanosomiasis.

The activity of diguanidino and 'reversed' diamidino 2,5-diarylfurans versus Trypanosoma cruzi and Leishmania donovani.

The in vitro activity of 20 dicationic molecules containing either diguanidino or reversed amidine cationic groups were evaluated versus Trypanosoma cruzi and Leishmania donovani. The most active compounds were in the reversed amidine series and six exhibited IC(50) values of less than 1 micro mol versus T. cruzi and five gave similar values versus L. donovani.

Antileishmanial dinitroaniline sulfonamides with activity against parasite tubulin

Novel dinitroaniline sulfonamides based on the herbicide oryzalin 3 were synthesized and evaluated for activity against the parasitic protozoan Leishmania donovani and against leishmanial tubulin, the putative antiparasitic target of oryzalin. A subset of these compounds possess more activity against both Leishmania and the target protein in vitro. Compound 20 displays improved potency against leishmanial tubulin and is 13.4-fold more active against L. donovani axenic amastigotes than oryzalin.

In vitro anti-uveal melanoma activity of phenolic compounds from the Egyptian medicinal plant Acacia nilotica

Anti-uveal melanoma activity-guided fractionation of the MeOH extract of Acacia nilotica pods resulted in the isolation of the new compound gallocatechin 5-O-gallate in addition to methyl gallate, gallic acid, catechin, catechin 5-O-gallate, 1-O-galloyl-β-D-glucose, 1,6-di-O-galloyl-β-D-glucose and digallic acid. The structures of the isolated compounds were elucidated on the basis of HRESIMS, NMR spectroscopy and CD data. In addition to uveal melanoma, the antiproliferative activities of the isolated compounds and the related compound epigallocatechin 3-O-gallate (EGCG) were evaluated against cutaneous melanoma, ovarian cancer, glioblastoma and normal retinal pigmented cells.

Antiparasitic Activity of C-Geranyl Flavonoids from Mimulus bigelovii

Bioactivity‐directed fractionation of the MeOH fraction of the extract of Mimulus bigelovii by means of an axenic Leishmania amastigote assay and chromatographic techniques resulted in the isolation of four C‐geranyl flavanones, diplacone (1), 3′‐O‐methyldiplacone (2), 4′‐O‐methyldiplacone (3), 3′‐O‐methyldiplacol (4), together with a geranylated flavone, cannflavin A (5). These compounds were separated from M. bigelovii for the first time. All compounds showed moderate antileishmanial activity against axenic Leishmania donovani amastigotes with IC50 values ranging from 4.8 to 14.6 μg/mL. The compounds were also tested against the related kinetoplastid parasite Trypanosoma brucei brucei and they showed activity with IC50 values ranging from 1.4 to 7.2 μg/mL. Copyright

Antiprotozoal Activities of Symmetrical Bishydroxamic Acids

Symmetrical bishydroxamic acids along with their sodium salts containing an alkyl spacer between two aromatic rings were synthesized, and their antiparasitic activities were evaluated. Bishydroxamic acids were conveniently prepared from the alkylation of methyl 4-hydroxybenzoate with various dihalo-alkane, -alkene, and -ether followed by reaction with hydroxylamine. Surprisingly, the bishydroxamic acids and their sodium salts possess strong inhibitory activities against Plasmodium falciparum parasites with IC50 values in the range of 0.26-3.2 microM. Bishydroxamic acid 3 and its sodium salt 12 also inhibit the growth of Leishmania donovani, albeit at higher concentrations. The corresponding biscarboxylic acids and bismethyl esters are inactive. Presumably, the ability of bishydroxamic acids to complex with metallic iron in hemoglobin may be responsible for antimalarial activity of these compounds.