Alkanediamide-Linked Bisbenzamidines Are Promising Antiparasitic Agents

Abstract

A series of 15 alkanediamide-linked bisbenzamidines and related analogs was synthesized and tested in vitro against two Trypanosoma brucei (T.b.) subspecies: T.b. brucei and T.b. rhodesiense, Trypanosoma cruzi, Leishmania donovani and two Plasmodium falciparum subspecies: a chloroquine-sensitive strain (NF54) and a chloroquine-resistant strain (K1). The in vitro cytotoxicity was determined against rat myoblast cells (L6). Seven compounds (5, 6, 10, 11, 12, 14, 15) showed high potency against both strains of T. brucei and P. falciparum with the inhibitory concentrations for 50% (IC50) in the nanomolar range (IC50 = 1–96 nM). None of the tested derivatives was significantly active against T. cruzi or L. donovani. Three of the more potent compounds (5, 6, 11) were evaluated in vivo in mice infected with the drug-sensitive (Lab 110 EATRO and KETRI 2002) or drug-resistant (KETRI 2538 and KETRI 1992) clinical isolates of T. brucei. Compounds 5 and 6 were highly effective in curing mice infected with the drug-sensitive strains, including a drug-resistant strain KETRI 2538, but were ineffective against KETRI 1992. Thermal melting of DNA and molecular modeling studies indicate AT-rich DNA sequences as possible binding sites for these compounds. Several of the tested compounds are suitable leads for the development of improved antiparasitic agents.

Antimicrobial Peptides (AMPs): Potential Therapeutic Strategy against Trypanosomiases?

“…Salvage chemotherapy or repositioning of established pharmacotherapeutic agents, with known activity and side-effect profiles, have been considered as candidates for the treatment of trypanosomiases [ 58 , 65 , 66 , 77 ]. Several of these repositioned drugs are commonly used as dietary supplements and to treat other diseases (bacterial and fungal infections, hypertension, depression, osteoporosis) [ 77 , 87 , 88 , 89 , 90 , 91 , 92 ]. Many studies with such drugs are in the preclinical phase for trypanosomiasis (using methodologies based on in vitro or animal studies), clinical trials, and described in case reports.…”

Novel lead compounds in pre-clinical development against African sleeping sickness

“…28 According to Vanden Eynde et al the toxicity of pentamidine could be reduced by replacing the dioxypentyl linker by a diamidealkyl linker. 40 The most promising derivatives 7, 8, and 9 ( Fig. 3) (IC 50 = 2-9 nM, T. b. brucei; CC 50 = 43.0 ≥ 100 μM, L6 cells) were tested in mice infected with drugsensitive and drug-resistant strains of T. b. brucei.…”

“…However, all compounds tested including pentamidine were ineffective against strain Ketri 1992 (refractory to diamidines). 40 Yang et al focused on potent diamidines with 10 ( Fig. 3) being the most selective scaffold.…”

Design and evaluation of poly-nitrogenous adjuvants capable of potentiating antibiotics in Gram-negative bacteria

“…11,12,14,20,21 In 2012 Katsu et al demonstrated that pentamidine (3, Fig. 1), an antiparasitic bisbenzamidine that works via DNA/ RNA disruption, 22,23 is not only capable of penetrating the OM of Gram-negative bacteria due to its polycationic and amphiphilic nature at physiological pH, but it is also able to potentiate activity of the aminocoumarin antibiotic novobiocin against EC. 24 Pentamidine's utility as an adjuvant has steadily been expanded over the last decade, and now it has been shown to be able to potentiate a wide range of Gram-positive antibiotics towards EC, 25 AB, 25 and Enterobacteriaceae 26 and non-antibiotics such as mitomycin C against clinical strains of EC, KP, PA, and AB.…”