Click Chemistry-Facilitated Structural Diversification of Nitrothiazoles, Nitrofurans, and Nitropyrroles Enhances Antimicrobial Activity against Giardia lamblia

Abstract

Giardia lamblia is an important and ubiquitous cause of diarrheal disease. The primary agents in the treatment of giardiasis are nitroheterocyclic drugs, particularly the imidazoles metronidazole and tinidazole and the thiazole nitazoxanide. Although these drugs are generally effective, treatment failures occur in up to 20% of cases, and resistance has been demonstrated in vivo and in vitro. Prior work had suggested that side chain modifications of the imidazole core can lead to new effective 5-nitroimidazole drugs that can combat nitro drug resistance, but the full potential of nitroheterocycles other than imidazole to yield effective new antigiardial agents has not been explored. Here, we generated derivatives of two clinically utilized nitroheterocycles, nitrothiazole and nitrofuran, as well as a third heterocycle, nitropyrrole, which is related to nitroimidazole but has not been systematically investigated as an antimicrobial drug scaffold. Click chemistry was employed to synthesize 442 novel nitroheterocyclic compounds with extensive side chain modifications. Screening of this library against representative G. lamblia strains showed a wide spectrum of in vitro activities, with many of the compounds exhibiting superior activity relative to reference drugs and several showing Ͼ100-fold increase in potency and the ability to overcome existing forms of metronidazole resistance. The majority of new compounds displayed no cytotoxicity against human cells, and several compounds were orally active against murine giardiasis in vivo. These findings provide additional impetus for the systematic development of nitroheterocyclic compounds with nonimidazole cores as alternative and improved agents for the treatment of giardiasis and potentially other infectious agents.

Treatment-refractory giardiasis: challenges and solutions

“…Many of the compounds displayed better activity in vitro than MTZ and nitazoxanide, with some of them being effective (<100 nM) against nitro drug-resistant Giardia lines. 86 Interestingly, in a murine infection model, the activities of the six selected most promising compounds did not correlate well with the in vitro activities. 86 This observation underlines the importance to evaluate carefully pharmacokinetic/pharmacodynamic properties when selecting compounds to further progress into optimization to clinical studies.…”

“…Systematic structural modifications of existing nitroheterocyclic drugs and BIs have been undertaken. 85 , 86 As an example, more than 400 new nitroheterocyclic derivatives were obtained by modifications of the imidazole ring using click chemistry. Many of the compounds displayed better activity in vitro than MTZ and nitazoxanide, with some of them being effective (<100 nM) against nitro drug-resistant Giardia lines.…”

Anti-GiardiaDrug Discovery: Current Status and Gut Feelings

“…However, further studies examining the in vivo activity of these derivatives and their activity against drug resistant parasites are needed. Indeed, a more recent study that investigated the biological activity of a library of nitrothiazole compounds against multiple Giardia parasite lines has demonstrated the importance of examining compound activity against multiple drug-resistant parasites . While this study identified multiple potent new nitrothiazole compounds, many displayed reduced activity against metronidazole resistant parasites, which varied considerably between lines.…”

“…While this study identified multiple potent new nitrothiazole compounds, many displayed reduced activity against metronidazole resistant parasites, which varied considerably between lines. As an example, one of the most potent nitrothiazoles in this work G-143 (EC 50 100 nM against 713 metronidazole sensitive parasites; Figure ), demonstrated a ∼65-fold higher EC 50 against the drug-resistant line WM-M2 and an ∼20-fold higher EC 50 against the drug-resistant line 713-M3 . Nevertheless, this study did identify compounds with improved potency and selectivity.…”

Antimicrobial resistance of the enteric protozoon Giardia duodenalis – A narrative review

“…In silico drug design offers new options of designing nitroheterocyclic drugs with therapeutic effects against giardiasis. In addition to nitroimidazoles, such nitroheterocyclic drugs also comprise nitropyrroles and nitrofurans [ 86 ]. The nitrofuran furazolidone has been shown in vitro to provide more severe damage than metronidazole to cyst stages of G. duodenalis , associated with morphological alterations like the presence of cavities, lamellar bodies as well as thread-like structures and inhibition of in vitro cyst differentiation [ 87 ].…”