Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group.
Histone deacetylase inhibitors (HDACi) are endowed with plethora of biological functions including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. Parsing the structure-activity relationship (SAR) for each disease condition is vital for long-term therapeutic applications of HDACi. We report in the present study specific cap group substitution patterns and spacer-group chain lengths that enhance the antimalarial and antileishmanial activity of aryltriazolylhydroxamates-based HDACi. We identified many compounds that are several folds selectively cytotoxic to the plasmodium parasites compared to standard HDACi. Also, a few of these compounds have antileishmanial activity that rivals that of miltefosine, the only currently available oral agent against visceral leishmaniasis. The anti-parasite properties of several of these compounds tracked well with their anti-HDAC activities. The results presented here provide further evidence on the suitability of HDAC inhibition as a viable therapeutic option to curb infections caused by apicomplexan protozoans and trypanosomatids.
Patil
Vishal
V
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
Guerrant
William
W
Chen
Po C
PC
Gryder
Berkley
B
Benicewicz
Derek B
DB
Khan
Shabana I
SI
Tekwani
Babu L
BL
Oyelere
Adegboyega K
AK
D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects; D007896:Leishmaniasis / Q000188:drug therapy; D008288:Malaria / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
D000962:Antimalarials; D000981:Antiprotozoal Agents; D056572:Histone Deacetylase Inhibitors; D014230:Triazoles; D006655:Histone Deacetylases