# Anti-Infective Properties, Cytotoxicity, and In Silico ADME Parameters of Novel 4′-(Piperazin-1-yl)benzanilides

## TL;DR

This study develops new compounds with anti-malaria and antibacterial properties, showing potential for treating drug-resistant infections.

## Contribution

The first synthesis and evaluation of 4′-(piperazin-1-yl)benzanilides with broad-spectrum anti-infective activity.

## Key findings

- A diarylthioether derivative showed strong activity against P. falciparum and Gram-positive/Gram-negative bacteria.
- Structure–activity relationships were established for the new compounds.
- Compounds met drug-likeness criteria and showed favorable pharmacokinetic properties.

## Abstract

Background: The benzamide MMV030666 from MMV’s Malaria Box Project, the starting point of herein presented study, was initially tested against various Plasmodium falciparum strains as well as Gram-positive and Gram-negative bacteria. It exhibits multi-stage antiplasmodial potencies and lacks resistance development. Methods: The favorable structural features from previous series were kept while the influence of the N-Boc-piperazinyl substituent per se, as well as its ring position and its replacement by various heteroaromatic rings, was evaluated. Thus, this paper describes the preparation of the MMV030666-derived 4′-(piperazin-1-yl)benzanilides for the first time, exhibiting broad-spectrum activity not only against plasmodia but also various bacterial strains. Results: A series of insightful structure–activity relationships were determined. Furthermore, pharmacokinetic and physicochemical parameters of the new compounds were determined experimentally or in silico. Drug-likeliness according to Lipinski’s rules was calculated as well. Conclusions: A diarylthioether derivative of the lead compound was promisingly active against P. falciparum and exhibited broad-spectrum antibacterial activity against Gram-positive as well as Gram-negative bacteria. It is considered for testing against multi-resistant bacterial strains and in vivo studies.