Exploration of Pyrazolo[1,5‐a]pyrimidines as Membrane‐Bound Pyrophosphatase Inhibitors

Abstract

Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying com-pounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure-activity relationships around a new scaffold having a pyrazolo[1,5-a]pyrimidine core. The most promising pyrazolo[1,5-a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.

In vitro enzymatic evaluation of some pyrazolo[1,5‐a]pyrimidine derivatives: Design, synthesis, antioxidant, anti‐diabetic, anti‐Alzheimer, and anti‐arthritic activities with molecular modeling simulation

“…Another example is the biological applications of 5‑aminopyrazole derivatives as antioxidant and antitumor agents (Fekri et al, 2022). During the past decade and depending on the above strategy, there has been an increasing interest in the synthesis of pyrazolopyrimidine‐based compounds due to their important and various biological applications (Ajeesh Kumar et al, 2017; Arias‐Gómez et al, 2021; Ayman et al, 2022; Burgart et al, 2020; El‐Sayed & Mohamed, 2021; Johansson et al, 2021; Salem et al, 2019) For example, the 2,5‐diphenyl‐pyrazolo[1,5‐ a ]pyrimidine derivative I exhibited antibacterial potency against Streptococcus mutans Gram‐positive and Pseudomonas aeruginosa Gram‐negative (Aggarwal et al, 2021). Trifluoromethyl‐phenyl‐pyrazolo[1,5‐ a ]pyrimidine derivative II showed antifungal activity against Alternaria solani (Zhang et al, 2016).…”

Functional and structural asymmetry suggest a unifying principle for catalysis in integral membrane-bound pyrophosphatases

“…(trypanosomiasis) and Toxoplasma gondii (toxoplasmosis) is a promising approach to combating these dieases (Zhang et al, 2018; Lemercier et al, 2002; Liu et al, 2014). Recently, we have developed non-phosphorus M-PPase inhibitors with the potential for further development into therapeutic molecules (Johansson et al, 2020, 2021; Vidilaseris et al, 2019).…”