Are basic and lipophilic chain groups highly required in leishmanicidal quinolines to favor the phagolysosome accumulation?

Abstract

A phagolysosome is a cytoplasmic body formed through the fusion of a phagosome with a lysosome during the phagocytosis process (Alexander and Vickerman, 1975). The phagolysosome is characterized by an internal acidic environment (pH 4.5–5.0) and an internal temperature of 37°C. This internal acidic condition plays an important role in the intracellular destruction of pathogens via enzymatic hydrolytic degradation (Nguyen and Yates, 2021). This body is crucial for the survival of Leishmania parasites within the host cell (Zilberstein, 2021). Leishmania is an intracellular parasite that cycles between the midgut of female sandfly vectors and phagolysosomes of mammalian hosts. The infection initiates with the transformation of the parasite found in the midgut of a sandfly into the flagellated promastigote form. Then the parasites are injected into the human skin during a sandfly blood meal and are rapidly phagocytosed by macrophages, which fuse with lysosomes to form phagolysosomes (Zilberstein, 2021). It is documented that the presence of a chemical component such as lipophosphoglycan (LPG) could be essential in the recognition of promastigote parasite by macrophage cells (Desjardins and Descoteaux, 1997; Moradin and Descoteaux, 2012). Once within the phagolysosome, promastigotes are differentiated to a smaller aflagellated intracellular amastigote form, which is favored by the extremely harsh environment inside the phagolysosome (Berman et al., 1979; Chang and Dwyer, 1976). The parasites at this stage survive and elude the host defense mechanism within the phagolysosome (Chang and Dwyer, 1976; Moradin and Descoteaux, 2012) and then proliferate by binary cell division and invade other macrophages or phagocytic (i.e. dendritic cells) or non-professional phagocytic (i.e. fibroblasts) cells. To elude the host immune defense, Leishmania parasites developed a mechanism directed to promote a shift in the macrophage polarization, from a defensive macrophage M1 to an attenuated macrophage M2 (Carneiro et al., 2021; Naderer and McConville, 2008; Tomiotto-Pellissier, et al., 2018), which allows their survival and proliferation inside phagolysosomes. Thus, the phagolysosome emerges as an attractive target for the development of leishmanicidal agents, and it is essential to design chemical structures that will be able to accumulate into the phagolysosome taking advantage of their internal acidic characteristic and highly lipophilic membrane. With this prelude in hand, the present article seeks to show the role of some physicochemical properties [e.g., ionization constant (pKa) and lipophilicity (log P)] to favor the accumulation of quinoline systems into the lysosome and to subsequently correlate these parameters with the in vitro leishmanicidal response against intracellular amastigotes.