Novel Hydrophilic Riminophenazines as Potent Antiprotozoal Agents

Abstract

SAR studies on a set of novel hydrophilic C-2 aminopyridinyl riminophenazines bearing variously functionalized basic side chains at C-3 were conducted. The novel compounds were evaluated for in vitro activity against two different species of Leishmania promastigotes, intramacrophage Leishmania amastigotes, chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, and also against mature-stage P. falciparum gametocytes. Their cytotoxicity was evaluated as well on BMDM cell lines. Most of the new compounds potently inhibited the growth of both genera of protozoa with IC 50 values in the high nanomolar range and good selectivities versus mammalian cells. Besides their potent activity against asexual intraerythrocytic stages of P. falciparum, three compounds showed potential as transmission-blocking agents. The key role of the hydrophilic C-2 aminopyridinyl substituent to improve the leishmanicidal activity and the influence of the length and the nature of the basic side chain on the antiprotozoal activity and cytotoxicity were underlined.

Clofazimine derivatives as potent broad-spectrum antiviral agents with dual-target mechanism

“…A total of 32 clofazimine derivatives, of which 22 were new, were prepared as depicted in Scheme 1 , Scheme 2 respectively. The synthesis of compounds 6a , 6b , 7a – c , 7l – o and 15b were reported previously [ [13] , [14] , [15] , [16] , [17] , [18] , [19] ].

Scheme 1 Reagents and conditions: (a) DFDNB, Et 3 N, ethanol, rt; (b) Substituted aniline or benzylamine or 5-amino-2-methoxypyridine, Et 3 N, THF, 64 °C; (c) Zn/acetic acid, ethanol, rt; (d) Air, ethanol, rt; (e) R 2 NH 2 , acetic acid, dioxane, 101 °C.

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“…Flash chromatography over silica gel was performed on Combiflash Rf 200 (Teledyne, Nebraska, USA). Compounds 6a , 6b , 7a – c , 7l – o and 15b were synthesized and identified by mp or 1 H NMR [ [13] , [14] , [15] , [16] , [17] , [18] , [19] ].…”

The Phenazine Scaffold Used as Cytotoxic Pharmacophore Applied in Bactericidal, Antiparasitic and Antitumor Agents

“…[258] Additionally, the more hydrophilic analog 5-(4-chlorophenyl)-3-{ [3-(dimethylamino)propyl]imino}-N-(pyridin-3-yl)-3,5-dihydrophenazin-2-amine (65) indicated high inhibition ability against both promastigotes of Leishmania infantum (IC 50 = 0.41 μM) and L. tropica (IC 50 = 0.77 μM), as well as D-10 (CQÀ S) and W-2 (CQÀ R) strains of Plasmodium falciparum with IC 50 values of 0.40 and 0.28 μM, respectively. [250,259] Recently, the riminophenazine 5-(4-chlorophenyl)-3-{[2-(4-methylpiperazin-1-yl)ethyl]imino}-N-(pyridin-3-yl)-3,5-dihydrophenazin-2-amine 66 (MU17) were identified as the new lead compounds for the riminophenazine-based targeted therapy against TNBC (IC 50 = 2.7 μM)) and Wnt-dependent cancers. This watersoluble compound displayed a 7-fold improved potency against Wnt signaling in TNBC cells resulting in on-target suppression of tumor growth in a patientderived mouse model of TNBC.…”

“…This watersoluble compound displayed a 7-fold improved potency against Wnt signaling in TNBC cells resulting in on-target suppression of tumor growth in a patientderived mouse model of TNBC. [259,260] Figure 8. Chemical structures of pyrifazimines and the biological activity of these compounds.…”

“…Besides, this analog demonstrated improved physicochemical properties and pharmacokinetic profiles with a short half‐life and less drug tissue accumulation than CFM [258] . Additionally, the more hydrophilic analog 5‐(4‐chlorophenyl)‐3‐{[3‐(dimethylamino)propyl]imino}‐ N ‐(pyridin‐3‐yl)‐3,5‐dihydrophenazin‐2‐amine ( 65 ) indicated high inhibition ability against both promastigotes of Leishmania infantum ( IC 50 =0.41 μ m ) and L. tropica ( IC 50 =0.77 μ m ), as well as D‐10 (CQ−S) and W‐2 (CQ−R) strains of Plasmodium falciparum with IC 50 values of 0.40 and 0.28 μ m , respectively [250,259] . Recently, the riminophenazine 5‐(4‐chlorophenyl)‐3‐{[2‐(4‐methylpiperazin‐1‐yl)ethyl]imino}‐ N ‐(pyridin‐3‐yl)‐3,5‐dihydrophenazin‐2‐amine 66 (MU17) were identified as the new lead compounds for the riminophenazine‐based targeted therapy against TNBC ( IC 50 =2.7 μ m )) and Wnt‐dependent cancers.…”