Benzimidazole derivatives endowed with potent antileishmanial activity

Abstract

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.

Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[d]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium falciparum Adenylosuccinate Lyase Receptor

“…Benzimidazole derivatives (substituted benzo[ d ]imidazol-1-yl)methyl)benzimidamides) were considered as potential analogues for AICAR due to similarities in chemical structure (Figure 1), and could be evaluated for their antimalarial propensity. Benzimidazole derivatives have been widely used in recent years due to their wide range of pharmacological activities including antimalarial, 8 antileishmanial, 9 analgesics, 10 anticancer, 11 antitumour, 12 antimicrobial, 13 anti-inflammatory, 14 antihepatitis C virus, 15 antihelmintic, 16 antibacterial 17 and antitrypanosomal 18 activities. Although several benzimidazole derivatives have been synthesised and developed into commercially available drugs, little is known about the design of the template as an inhibitor against P falciparum ADSL ( Pf ADSL).…”

Design, Synthesis and In Vitro Investigation of Novel Basic Celastrol Carboxamides as Bio-Inspired Leishmanicidal Agents Endowed with Inhibitory Activity against Leishmania Hsp90

“…In the quest for novel antiprotozoal agents, the identification of novel targets and mechanisms of actions is highly cherished to surpass the insurgence and spread of drug resistant parasite strains. Not to be forgotten, the cytotoxicity and the lack of selectivity of action of modern and classical leishmanicidal agents is well-known and represents a harming issue of public health [ 13 , 14 , 15 , 55 , 56 , 58 ].…”

“…Cells were washed and infected with metacyclic L. infantum promastigotes at a macrophage/promastigote ratio of 1/10 for 24 h. Cell monolayers were then washed and incubated in the presence of test compounds for 72 h. Slides were fixed with methanol and stained with Giemsa. The percentage of infected macrophages in treated and non-treated cells was determined by light microscopy [ 55 , 56 ].…”

A Comprehensive Account on Recent Progress in Pharmacological Activities of Benzimidazole Derivatives

“…Keurulainen et al ( Keurulainen et al, 2015 ) synthesized several 2-arylbenzimidazole derivatives and proclaimed extensive inhibitory property of compounds 343–344 against axenic amastigotes of Leishmania donovani . Tonelli and co-workers ( Tonelli et al, 2018 ) reported in vitro antileishmanial activity of derivatives 345–346 with IC 50 values of 3.70 and 0.19 µM, respectively against L. tropica , and 4.76 and 0.64 µM, respectively against L. infantum . In another research, a total of 28 N -benzyl-1 H -benzimidazol-2-amine derivatives, where compounds 347–348 showed significant ( p < 0.05) antileishmanial activity against the amastigote of L. mexicana and L. braziliensis with IC 50 values of 2.62 and 3.21 µM, respectively, and their activity was 5.8 and 4.8 times better than standard miltefosine (IC 50 = 15.34 µM) ( Nieto-Meneses et al, 2018 ).…”