Gold(I) Phosphine Derivatives with Improved Selectivity as Topically Active Drug Leads to Overcome 5-Nitroheterocyclic Drug Resistance in Trichomonas vaginalis

Abstract

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure−activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1−C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.

Novel Treatment Approaches to Combat Trichomoniasis, a Neglected and Sexually Transmitted Infection Caused by Trichomonas vaginalis: Translational Perspectives

“…The trichomonacidal effect was confirmed following compound oral administration for 4 days, without any adverse effects [36]. This approach was also used by Natto [32] and Miyamoto [15] to evaluate the trichomonacidal activity of the most effective compounds. Deazopurine nucleoside analogue 7-deaza,7-(3,4-dichlorophenyl)adenosine (FH3147) presented EC 50 value of 0.029 µM against T. vaginalis [32].…”

“…Deazopurine nucleoside analogue 7-deaza,7-(3,4-dichlorophenyl)adenosine (FH3147) presented EC 50 value of 0.029 µM against T. vaginalis [32]. The screening of compounds containing gold highlighted the anti-T. vaginalis activities of the derivatives (tri-n-ethylphosphine)gold(I) chloride ( 4) and (tri-n-methylphosphine)-gold(I) chloride (10) [15]. The use of methylene blue and light-emitting diodes was evaluated against MTZsensitive and -resistant T. vaginalis isolates.…”

Biological Activity of Gold Compounds against Viruses and Parasitosis: A Systematic Review

“…Plasmonium falciparum and Leishmania infantum Gold(I) complexes combined with triclosan [41,42] Protozoa and Helminth infections Gold(I) complex [43] Leishmania major, Toxoplasma gondii and Trypanosoma brucei parasites Gold(I)-carbene complexes [44] Trichomonas vaginalis Gold Complexes: gold(I) phosphine derivatives [45] Helmintic Gold(I) nanoparticles [46] L. amazenensis and L. braziliensis Gold(I) and gold(III) complexes [47] BioChem 2022, 2, FOR PEER REVIEW 7…”

“…All of the tested gold(I) complexes inhibited TrxR in T. vaginalis, with the most potent compounds exhibiting IC50 values of <50 nM, little difference in the inhibition of two of the most abundantly expressed TrxR isoforms, and good correlations between the inhibition of individual isoforms and the inhibition of total cellular TrxR activity. Two of the compounds with increased activity against whole cells compared to TrxR were gold(I)-bis-phosphines [45]. Koko et al synthesized a series of cationic gold(I) carbenes with various 4,5-diarylimidazolylidene as ligands (Figure 9) to test their activity against Leishmania major, Toxoplasma gondii and Tripanossoma brucei parasites [44].…”

Design, Synthesis, and Preclinical Activity in Ovarian Cancer Models of New Phosphanegold(I)-N-heterocyclic Carbene Complexes

“…The investigation of anticancer activity of gold­(I) complexes of N-heterocyclic carbenes (NHCs) is a rapidly growing field of research in organometallic chemistry. − This may be correlated to their enhanced stability under biological conditions that arises on the basis of strong σ-donation of NHCs, which is comparable to that of phosphanes. ,,− The lipophilicity of the gold-NHCs could be tuned more easily by modulating the nature of the substituents of the heterocyclic rings. , The antirheumatic gold­(I)-phosphane drug auranofin [(2,3,4,6-tetra- O -acetyl- l -thio-β- d -glycopyranosato- S -)­(triethylphosphane)­gold­(I)] represents the guide compound for the anticancer gold­(I) compounds. − Recently, several gold­(I)-phosphane complexes have been shown to exhibit promising antitumor activity. − The crystal structure analyses of NHC-gold­(I) complexes reveal a linear geometry around gold­(I). ,− ,, Some of these complexes are characterized by aurophilic interactions. , …”