Front Cover: Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine‐ and Furopyridine‐Based Anti‐infective Agents against Trypanosomiases (6/2021)

Abstract

The Front Cover shows efforts among Brazilian, American, and European researchers to combat neglected tropical diseases. New heterocyclic compounds based on imidazopyridine/pyrimidine and furopyridine cores originating from Brazil travel to the USA and Europe to be developed as anti‐infective agents against Trypanosomiases. By exploring the chemical diversity at eight different positions of the central core, we obtained various heterocyclic compounds having significant potential for anti‐trypanosomiases drug discovery. More information can be found in the Full Paper by Daniel G. Silva, Flavio S. Emery et al. Cover design by Daniel Gedder Silva.

Development of Novel Isoindolone‐Based Compounds against Trypanosoma brucei rhodesiense

“…Recently, new heterocyclic compounds have been discovered through phenotypic screening as potential antitrypanosomal agents, marking renewed hope to treat sleeping sickness. [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ] This approach has demonstrated to be successful for the discovery of first‐in‐class drugs providing an advantage in identifying compounds that are active against the whole cell, being especially efficient in infectious disease drug development. [14] We contributed to this by the development of a large number of new heterocyclic compounds having different ring systems[ 8 , 13 , 14 ] that were assayed against different Trypanosoma species.…”

“…Our previous structure‐activity relationship studies (SARs) revealed that the presence of the urea group attached to the 7‐position (R 1 , hit compound 1 ) of the fused ring system proved to be essential for bioactivity; compounds with aromatic groups in region R 2 (hit compound 2 ) were found to be more effective than aliphatics in increasing potency; amide, ester, and organic acid functions can be tolerated at the 3‐position (hit compound 3 ). [ 8 , 13 ]…”

“…Our previous structure-activity relationship studies (SARs) revealed that the presence of the urea group attached to the 7position (R 1 , hit compound 1) of the fused ring system proved to be essential for bioactivity; compounds with aromatic groups in region R 2 (hit compound 2) were found to be more effective than aliphatics in increasing potency; amide, ester, and organic acid functions can be tolerated at the 3-position (hit compound 3). [8,13] Applying standard medicinal chemistry principles to design new compounds, we established the following requirements for the antiparasitic activity: a urea moiety linked to bulky amino-alkyl groups at the region R 1 (combinations of hit compounds 1 and 3), an aromatic ring at the region R 2 , and a carbonyl group linked to the nitrogen atom (lactam); forming an isoindolone ring. An isoindolone ring is the base scaffold for the commercial drug Lenalidomide (hit compound 4), used to treat multiple myeloma.…”

“…As such, there is an urgent need to replace the currently available toxic drugs with orally bioavailable, highly potent, non‐toxic alternatives. Recently, new heterocyclic compounds have been discovered through phenotypic screening as potential antitrypanosomal agents, marking renewed hope to treat sleeping sickness [4–13] . This approach has demonstrated to be successful for the discovery of first‐in‐class drugs providing an advantage in identifying compounds that are active against the whole cell, being especially efficient in infectious disease drug development [14] .…”

“…[4][5][6][7][8][9][10][11][12][13] This approach has demonstrated to be successful for the discovery of first-in-class drugs providing an advantage in identifying compounds that are active against the whole cell, being especially efficient in infectious disease drug development. [14] We contributed to this by the development of a large number of new heterocyclic compounds having different ring systems [8,13,14] that were assayed against different Trypanosoma species. Some examples are presented in Figure 1.…”