Discovery and Characterization of 2-Nitro-5-(4-(phenylsulfonyl)piperazin-1-yl)-N-(pyridin-4-ylmethyl)anilines as Novel Inhibitors of the Aedes aegypti Kir1 (AeKir1) Channel

Abstract

Mosquito-borne arboviral diseases such as Zika, dengue fever and chikungunya are transmitted to humans by infected adult female Aedes aegypti mosquitoes and affect a large portion of the world's population. The Kir1 channel in Ae. aegypti (AeKir1) is an important ion channel in the functioning of mosquito Malpighian (renal) tubules and one that can be manipulated in order to disrupt excretory functions in mosquitoes. We have previously reported the discovery of various scaffolds that are active against the AeKir1 channel. Herein we report the synthesis and biological characterization of a new 2-nitro-5-(4-(phenylsulfonyl) piperazin-1-yl)-N-(pyridin-4ylmethyl)anilines scaffold as inhibitors of AeKir1. This new scaffold is more potent in vitro compared to the previously reported scaffolds, and the molecules kill mosquito larvae.

Further SAR on the (Phenylsulfonyl)piperazine Scaffold as Inhibitors of the Aedes Aegypti Kir1 (AeKir) Channel and Larvicides

“…Having identified a number of potent AeKir inhibitors, we next screened a selection of these compounds for larvae toxicity at 100 µM and compared their efficacies to previously reported VU854. 16 As with other compounds, the new analogs had limited activity at 24 h (<25%, data not shown); however, many of the new analogs had significant mortality at 48 h ( Figure 2). Compounds 8 (100%), 9p (99%) and 12d (98%) showed significantly greater mortality at 48 h compared to VU854 (shown in red, Figure 2).…”

“…Compounds 8 (100%), 9p (99%) and 12d (98%) showed significantly greater mortality at 48 h compared to VU854 (shown in red, Figure 2). 16 A number of other compounds (9n, 9q, 9s, 12a and 12b) were similarly efficacious as VU854 (shown in grey, Figure 2), whereas others were less efficacious than VU854 (shown in blue, Figure 2). These results are intriguing as compounds that are active in the larval toxicity assay are not the most potent in vitro (e.g., 8) which raises questions to whether a compound such as 8 is more permeable versus other, more potent, compounds (e.g., 9k).…”

Further SAR on the (Phenylsulfonyl)piperazine Scaffold as Inhibitors of the Aedes Aegypti Kir1 (AeKir) Channel and Larvicides

“…The synthetic scheme for the synthesis of the 4-nitrophenylpiperazine analogs has been previously reported and is shown in Scheme 1. 16 Table 1 procedures are compiled in the Supplemental Information. 16 Scheme 1.…”

“…16 Table 1 procedures are compiled in the Supplemental Information. 16 Scheme 1. General synthetic scheme for analogs.…”

“…[12][13][14][15] More recently, we discovered a new (phenylsulfonyl)piperazine scaffold with superior in vitro potency against AeKir in both a Thallium-flux high-throughput assay as well as in patch clamp assays ( Figure 1). 16 Herein we report further efforts on the structure-activity relationships around this scaffold and their effects on toxicity against mosquito larvae.…”