Triphenylmethane Derivatives Have High In Vitro and In Vivo Activity against the Main Causative Agents of Cutaneous Leishmaniasis

Abstract

The current standard of care for cutaneous leishmaniasis (CL) is organic antimonial compounds, but the administration of these compounds is complicated by a low therapeutic - toxic index, as well as parenteral administration. Thus, there is an urgent need for the development of new and inexpensive therapies for the treatment of CL. In this study, we evaluate the activity of the triphenylmethane (TPM) class of compounds against three species of Leishmania which are pathogenic in humans. The TPM have a history of safe use in humans, dating back to the use of the original member of this class, gentian violet (GV), from the early 20th century. Initially, the in vitro efficacy against Leishmania (Viannia) braziliensis, L. (Leishmania) amazonensis and L. (L.) major of 9 newly synthesized TPM, in addition to GV, was tested. Inhibitory concentrations (IC) IC50 of 0.025 to 0.84 µM had been found in promastigotes in vitro assays. The four most effective compounds were then tested in amastigote intracellular assays, resulting in IC50 of 0.10 to 1.59 µM. A high degree of selectivity of antiparasitic activity over toxicity to mammalian cells was observed. Afterwards, GV and TPM 6 were tested in a topical formulation in mice infected with L. (L.) amazonensis leading to elimination of parasite burdens at the site of lesion/infection. These results demonstrated that TPM present significant anti-leishmanial activities and provide a rationale for human clinical trials of GV and other TPM. TPM are inexpensive and safe, thus using them for treatment of CL may have a major impact on public health.

Gentian Violet: a 19th century drug re‐emerges in the 21st century

“…Hundreds of thousands of patients have received blood transfusions containing GV, without side effects and without any reported cases of transmissible Chagas’ disease . A recent study found that GV was effective against the protozoa Leishmania , the causative agent of cutaneous leshmaniasis, both in vitro and in vivo in a mouse model . Gentian violet has also been used historically to treat the parasitic nematodes Strongyloides and Enterobium (pinworm) .…”

Multiple Reaction Pathways Operating in the Mechanism of Vinylogous Mannich‐Type Reaction Activated by a Water Molecule

“…Although some compounds presented moderate cytotoxicity (CC 50 =4.1 ( 7 b ), 4.3 ( 7 e ), and 3.4 ( 7 f ) μ M ), all compounds except 7 f (SI=67) displayed high selectivity indices (SI>100). Biological efficacy is generally considered to not be due to in vitro cytotoxicity when an SI value is ≥10 18. Consequently, these results suggest that the activity exhibited by compounds 7 a – f is unlikely due to general cellular toxicity but rather to specific antiplasmodial activity.…”

The topical treatment of old world cutaneous leishmaniasis with gentian violet along with cryotherapy: a pilot single-blind randomized controlled clinical trial

“…In addition to its antibacterial activity, GV has antimycotic, antiviral, antihelminthic, and antitrypanosomal effects 6 . Although the results of the study that evaluated in vitro and in vivo antileishmanial activity of GV and 10 other TPMs were promising 7 , to the best of our knowledge, no clinical trial has been conducted to assess the efficacy of GV.…”

“…de Souza Pietra et al 7 tested 9 synthetic triphenylmethane derivatives along with GV on Leishmania (L.) amazonensis, Leishmania (V.) braziliensis, and Leishmania major in vitro. GV was the most effective agent in this study.…”

“…GV was the most effective agent in this study. In BALB/c mice infected with Leishmania (L.) amazonensis and subsequently treated with 1% GV gel twice daily, no parasite was detected after 20 days of treatment 7 .…”