Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group

Abstract

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.

Molecular architecture of zinc chelating small molecules that inhibit spliceosome assembly at an early stage

“…These data imply that potential targets of these compounds also include proteins involved in the assembly of the A complex. Remarkably, compound 24 has an HDAC inhibition activity 15 times higher than that of compound 25 (Table 1; Patil et al 2010), yet both compounds stalled spliceosome assembly to approximately the same extent. Another intriguing observation is the fact that compound 9 (Supplemental Table S1), an analog of 24 with a single methylene chain deletion and a more than eightfold stronger HDAC inhibition than 24 (Chen et al 2008), was not identified as a splicing inhibitor in the primary screen.…”

“…However, the exact relationship between zinc chelation, protein acetylation state, and splicing inhibition is not clear, as only a limited set of HDAC inhibitors (HDACis) was screened. In the present work, we sought to clarify this relationship by screening a HDACi library that was structurally more diverse (Chen et al 2008;Canzoneri et al 2009;Oyelere et al 2009;Mwakwari et al 2010a,b;Patil et al 2010). We report here the elucidation of unique molecular features that confer splicing inhibition upon zinc-chelating agents with HDAC inhibition activity.…”

“…To this end, we first screened a small (63-member), yet structurally diverse HDACi library (see Supplemental Table S1 for the structures) at 100 mM using a conventional in vitro splicing assay. The HDAC inhibition activity of compounds in the screened library against HDAC1 and HeLa cell nuclear extract HDACs ranges from single digit-to mid-nanomolar (Chen et al 2008;Canzoneri et al 2009;Oyelere et al 2009;Mwakwari et al 2010a;Patil et al 2010). Despite their potency, these HDACis did not broadly inhibit splicing.…”

“…The screening of the HDACi library Patil et al 2010) for splicing inhibition identified 6-methoxynaphthalen-2-yl hydroxamates 24 and 25 as small molecules that inhibit spliceosome assembly at an early stage, to about the same extent, with IC 50 values close to 130 mM (Table 1). These data provided an initial indication that the inhibition of splicing may not be due to the targeting of HDACs.…”

Synthesis of 6-Amino-5-cyano-1,4-disubstituted-2(1H)-Pyrimidinones via Copper-(I)-catalyzed Alkyne-azide ‘Click Chemistry’ and Their Reactivity

“…Amongst the various classes of nitrogen heterocycles, 1,2,3-triazoles and their derivatives deserve special recognition due to their wide usage in industrial applications as dyes, photographic materials, corrosion inhibitors and as herbicidal, fungicidal and antibacterial agrochemicals [5,6]. Several members of the 1,2,3-triazole family exhibit a broad spectrum of antiinfectious properties such as antimicrobial [7], anti-HIV [8], anti-allergic [9] and antimalarial activities [10]. On the other hand, 2(1H)-pyrimidinones also show significant biological activities [11].…”