A “Golden Age” for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system

Abstract

Leishmaniasis is one of the most neglected diseases worldwide and is considered a serious public health issue. The current therapeutic options have several disadvantages that make the search for new therapeutics urgent. Gold compounds are emerging as promising candidates based on encouraging in vitro and limited in vivo results for several AuI and AuIII complexes. The antiparasitic mechanisms of these molecules remain only partially understood. However, a few studies have proposed the trypanothione redox system as a target, similar to the mammalian thioredoxin system, pointed out as the main target for several gold compounds with significant antitumor activity. In this review, we present the current status of the investigation and design of gold compounds directed at treating leishmaniasis. In addition, we explore potential targets in Leishmania parasites beyond the trypanothione system, taking into account previous studies and structure modulation performed for gold‐based compounds.

Current leishmaniasis drug discovery

“…77 In addition to the compounds found in clinical trials and the recent efforts to obtain new chemical entities able to overcome the issues related to the current treatment, such as toxicity, adverse effects, and advent of resistance, many synthesized agents, natural drugs or semisynthetic derivatives have been reported with remarkable antileishmanial activities, offering great potential for the future development of new antileishmanial chemotherapeutic drugs. [79][80][81][82][83][84][85][86][87][88][89] As most of the above cited studies indicate, the main strategy used to obtain currently available drugs is known as the phenotypic approach, when a new drug prototype is obtained without any knowledge about its target or specific function against the disease. 78 The screening of large libraries of drug candidates to obtain a hit compound and then elaborate their mechanisms of action has been successful in drug discovery but delays the progress to find the best possible prototype for that specific target.…”

“…In addition to the compounds found in clinical trials and the recent efforts to obtain new chemical entities able to overcome the issues related to the current treatment, such as toxicity, adverse effects, and advent of resistance, many synthesized agents, natural drugs or semisynthetic derivatives have been reported with remarkable antileishmanial activities, offering great potential for the future development of new antileishmanial chemotherapeutic drugs. 79–89…”

Nanomedicine-based strategies to improve treatment of cutaneous leishmaniasis

“…Parasitic resistance can be avoided by using drug-loaded surface-modified nano-DDS systems (mannosylated or thiolated) [49]. Nanoparticles such as gold complexes have emerged as anti-leishmanial agents whereby gold-based drugs exhibited immunomodulation activity, thioredoxin reductase inhibition and redox imbalance [50]. Another targeting approach for CL is host-directed therapies aiming at modulating the severity of CL, controlling the inflammatory response rather than solely restraining parasite replication.…”

“…Open Sci. 9: 220058 immunomodulation activity, thioredoxin reductase inhibition and redox imbalance [50]. Another targeting approach for CL is host-directed therapies aiming at modulating the severity of CL, controlling the inflammatory response rather than solely restraining parasite replication.…”

Synthesis, Characterization, and Antileishmanial Activity of Neutral Gold(I) Complexes with N-heterocyclic Carbene Ligands Bearing Sulfur-Containing Side Arms

“…One target for antileishmanial drugs is trypanothione reductase (TR), a crucial redox enzyme in Leishmania. , TR contains active-site thiol groups; thus, thiophilic metal-based compounds can potentially serve as selective inhibitors of TR. Gold complexes are proposed to block active site cysteine groups in thiol-dependent enzymes.…”