Zircon ages, Sr-Nd-Hf isotopic compositions, and geochemistry of granitoids associated with the northern ophiolite melange of Central Cuba: Tectonic implication for Late Cretaceous magmatism in the Northwestern Caribbean

Abstract

<h3>Abstract</h3> Tuberculosis remains one of the leading causes of death from a single infectious agent, surpassing both AIDS and malaria. In recent years, two bicyclic nitroimidazole drugs, delamanid and pretomanid have been approved to treat this airborne infection. This has spurred a renewed interest in developing new and improved nitroimidazole analogs. We have previously identified a new bicyclic heteroaromatic subclass, the nitroimidazopyrazinones, with substituted analogs showing promising activity against <i>Mycobacterium tuberculosis</i> under both aerobic and hypoxic environments. A second generation of nitroimidazopyrazinones with extended biaryl side chain also possessed good antiparasitic activity against <i>Trypanosoma brucei brucei</i> and <i>Trypanosoma cruzi</i>, suggesting the utility of this new scaffold for development into potential candidates against both tuberculosis and the kinetoplastid parasites which cause neglected tropical diseases. In this study, we further evaluated the properties of nitroimidazopyrazinone derivatives by assessing their selectivity against different mycobacterial species, measuring their reduction potential, and determining the kinetic parameters as substrates of the deazaflavin-dependent nitroreductase (Ddn), which is the activating enzyme of delamanid and pretomanid in <i>M. tuberculosis</i>. We also conducted an <i>in vivo</i> evaluation of a lead compound, MCC8967 that demonstrated a favorable pharmacokinetic profile, with good oral bioavailability and efficacy in an acute <i>M. tuberculosis</i> infection model. Two other promising compounds MCC9481 and MCC9482, with good <i>in vitro</i> activity (IC₅₀ = 0.016 and 0.10 µM, respectively) against <i>T. cruzi</i>, the causative agent for Chagas diseases, were similarly tested for <i>in vivo</i> activity. These compounds also exhibited good oral bioavailability, and transiently reduced the acute-stage parasite burden by &gt;98‒99% at doses of 50 mg/kg once or twice daily, similar to benznidazole at 100 mg/kg once daily. Overall, we have demonstrated that active nitroimidazopyrazinones have potential to be developed as clinical candidates against both tuberculosis and Chagas disease. <h3>Author Summary</h3> Tuberculosis and parasitic infections continue to impose a significant threat to public health and economic growth worldwide. Most of the efforts to control these diseases still rely on drug treatments with limited effectiveness and significant side effects. There is now an urgent need to develop new treatments to combat these infections. Here, we report the <i>in vitro</i> and <i>in vivo</i> profile of a new bicyclic nitroimidazole subclass, namely nitroimidazopyrazinones, against mycobacteria and <i>Trypanosoma cruzi</i>. We found that derivatives with monocyclic side chains are selective against <i>Mycobacterium tuberculosis</i>, the causative agent of tuberculosis, but not active against other nontuberculosis mycobacteria. In an acute mouse model, they were able to reduce the bacterial load in lungs via oral administration. From a biochemistry perspective, we demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in <i>M. tuberculosis</i>. We also showed that derivatives with extended biaryl side chain were effective in suppressing infection in an acute <i>T. cruzi</i> infected murine model, with satisfactory oral bioavailability. These findings improve the understanding of the biological profile of nitroimidazopyrazinones for further development as potential antitubercular and antiparasitic agents.