In Vitro and In Vivo Studies of the Trypanocidal Effect of Novel Quinolines

Abstract

Therapies for human African trypanosomiasis and Chagas disease, caused by and, respectively, are limited, providing minimal therapeutic options for the millions of individuals living in very poor communities. Here the effects of 10 novel quinolines are evaluated and by phenotypic studies using and models. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties revealed that most molecules did not infringe on Lipinski's rules, which is a prediction of good oral absorption. These quinolines showed high probabilities of Caco2 permeability and human intestinal absorption and low probabilities of mutagenicity and of hERG1 inhibition. screens against bloodstream forms of demonstrated that all quinolines were more active than the reference drug (benznidazole [Bz]), except for DB2171 and DB2192, with five (DB2187, DB2131, DB2186, DB2191, and DB2217) displaying 50% effective concentrations (ECs) of <3 μM (4-fold lower than that of Bz). Nine quinolines were more effective than Bz (2.7 μM) against amastigotes, showing ECs ranging from 0.6 to 0.1 μM. All quinolines were also highly active against African trypanosomes, showing ECs of ≤0.25 μM. The most potent and highly selective candidates for each parasite species were tested in models. Results for DB2186 were promising in mice with and infections, reaching a 70% reduction of the parasitemia load for, and it cured 2 out of 4 mice infected with DB2217 was also active and cured all 4 mice (100% cure rate) with infection.

Quinolines and Quinolones as Antibacterial, Antifungal, Anti-virulence, Antiviral and Anti-parasitic Agents

“…18) were evaluated against bloodstream forms of T. cruzi. Nine quinolines were more effective against amastigotes than benznidazole (EC 50 ¼ 2.7 μM) and they showed EC 50 values ranging from 0.6 to 0.1 μM (Nefertiti et al 2018). All examined quinolines were highly active in vitro against African trypanosomes, showing EC 50 values 0.25 μM.…”

Recent synthetic efforts in the preparation of 2-(3,4)-alkenyl (aryl) quinoline molecules towards anti-kinetoplastid agents

“…6C), which were more active than the reference drug (benznidazole) in vitro screens against bloodstream forms of T. cruzi. 116 They displayed EC 50 < 3 mM (<4-fold than benznidazole). Among them, quinolines 67 and 69 were tested in vivo models.…”

“…The synthesis of key 7-amino-2-phenylquinoline precursor was achieved in 3 steps through the Friedländer reaction starting with 4-bromo-2nitrobenzaldehyde. 116 In this context, it should be commented that there are still few efficient, direct synthesis for C-4 unsubstituted 2-arylquinolines using 3-C Povarov reaction of anilines, aromatic aldehydes and rich electron alkenes (e.g., alkyl vinyl ethers or N-vinyl amides). [117][118][119][120] that could be a good alternative route to quinolines 65-69.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…DB2186 reached 70% reduction of the parasitemia load in mice infected by Y strain. [ 111 ] Sphingosine kinase inhibitor N,N-dimethylsphingosine (DMS) DMS blocked sphingosine-1-phosphate production, a cell mediator during inflammatory responses, and exhibited anti-parasitic activity in vitro and in vivo and immunomodulatory actions in chronically infected mice. [ 112 ] Squaramides Squaramides New long-chain squaramides displayed in vitro and in vivo activity with low toxicity [ 55 , 113 ] Terpene and terpenoid derivatives Terpenoid derivates Synthesized terpenoid derivates displayed in vitro anti- T. cruzi activity and nontoxic effects upon host cells.…”

“…96 In addition, tetraamines were able to inhibit iron superoxide dismutase and trypanothione reductase of T. cruzi and presented activity in vitro and in vivo with low toxicity. 97 Other classes as antimicrobial peptides; 98,99 copper 100 or ruthenium [101][102][103][104] complexes, compounds that impact on purine salvage pathway, [105][106][107] oxaboroles, 56,57 oxamates, [108][109][110] quinolines, 111 sphingosine kinase inhibitor, 112 squaramides, 55,113 terpene and terpenoid derivatives 55 and proteasome inhibitors, 114,115 revealed interesting results, impacting the evolution of T. cruzi infection (Table 1), but the mechanisms are not well known. Figure 4 shows schematic representation of the main drug targets identified in T. cruzi.…”