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Trypanosomatids are the etiologic agents of numerous parasitic diseases that cause significant morbidity and mortality in millions of people and animals around the world. Approved antitrypanosomatid agents are limited by several drawbacks, such as severe toxicity, lengthy treatment, need for hospitalization, and susceptibility to drug resistance. Consequently, parasitic diseases remain a substantial public health problem, and new drugs are required, especially drugs suitable for rural health systems that have limited resources. In an attempt to find antitrypanosomatid agents to address this problem, we report here on the synthesis and biological efficacy of ferrocene derivatives of nifuroxazide and nitrofurazone, which were designed by replacing the nitrofuran scaffold within their structures with the ferrocene moiety. The 1,2‐disubstituted ferrocene intermediates 8 and 9, featuring amine and carboxaldehyde groups, exhibited the best in vitro antiamastigote activity against Leishmania major strain NIH S and Leishmania donovani strain 9515, respectively. Ferroxazide derivative 15 was revealed as a mammalian cell nontoxic hit compound against Trypanosoma congolense strain IL3000 trypomastigotes; however, no in vivo treatment efficacy was observed against T. congolense strain IL3000‐infected BALB/c mice during a preliminary animal study. The synthesized ferrocene derivatives were poorly soluble in the in vitro and in vivo testing media, hindering uniform sampling and dosing. This study's outcome indicates that replacing the 5‐nitrofuran moiety with ferrocene did not increase antitrypanosomatid activity compared to the nitrofuran parent drugs nifuroxazide and nitrofurazone. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a zoonotic disease prevalent in 83–92 countries. This disease's current treatments are unsatisfactory because of a variety of shortcomings, including serious toxicity, variable efficacy, painful administration, and the occurrence of parasite resistance to these antileishmanial agents. The abovementioned limitations have urged the development of novel, reliable, and affordable agents to treat leishmaniasis. Ferrocenylazine derivatives were therefore synthesized for activity screening against Leishmania major and Leishmania donovani cell cultures. This emphasizes the urgent need for new effective antileishmanial agents. In search for such therapeutics, we synthesized and evaluated in vitro the antileishmanial activity of a series of azine derivatives based on the organometallic compound ferrocene. Two ferrocenylaldazines, 2l and 2q, were uncovered as mammalian cell nontoxic antileishmanial early leads, expressing submicromolar activity with IC50 values of 0.78 ± 0.03 and 0.46 ± 0.03 μM, respectively, against amastigote of L. donovani. Ferrocenylazines may therefore act as potential new antileishmanial agents, and the next objective will be the identification of the involved biological targets. [ABSTRACT FROM AUTHOR]

Leishmaniasis and cancer are two deadly diseases that plague the human population. There are a limited number of drugs available for the treatment of these diseases; however, their overuse has resulted in pathogenic resistance. Recent studies have indicated the repurposing of nitro‐containing compounds to be a new avenue into finding new treatments. In this study, new nitrofuranyl sulfonohydrazide derivatives were synthesized and evaluated for their in vitro antileishmanial and anticancer activities. The analogue 2h, featuring biphenyl moiety exhibited selective (SI > 10) submicromolar activity (IC50 0.97 μM) against acute promyelocytic leukemia cells hence was identified anticancer hit. This study revealed no antileishmanial hit. However, several promising analogues were uncovered and are worthy of further structural modifications to improve their toxicity and bioactivity profiles. [ABSTRACT FROM AUTHOR]

Over the past few years, great progress has been made in the development of high‐affinity adenosine A1 and/or A2A receptor antagonists—promising agents for the potential treatment of Parkinson's disease. Unfortunately, many of these compounds raise structure‐related concerns. The present study investigated the effect of ring closures on the rA1/A2A affinity of compounds containing a highly reactive α,β‐unsaturated carbonyl system, hence providing insight into the potential of heterocycles to address these concerns. A total of 12 heterocyclic compounds were synthesised and evaluated in silico and in vitro. The test compounds performed well upon qualitative assessment of drug‐likeness and were generally found to be free from potentially problematic fragments. Most also showed low/weak cytotoxicity. Results from radioligand binding experiments confirm that heterocycles (particularly 2‐substituted 3‐cyanopyridines) can replace the promiscuous α,β‐unsaturated ketone functional group without compromising A1/A2A affinity. Structure–activity relationships highlighted the importance of hydrogen bonds in binding to the receptors of interest. Compounds 3c (rA1Ki = 16 nM; rA2AKi = 65 nM) and 8a (rA1Ki = 102 nM; rA2AKi = 37 nM), which both act as A1 antagonists, showed significant dual A1/A2A affinity and may, therefore, inspire further investigation into heterocycles as potentially safe and potent adenosine receptor antagonists. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a vector-borne, parasitic disease affecting millions of people and animals worldwide. Current therapeutic options have proven to be ineffective in both treating the disease and preventing its spread. As a result, new drugs must be developed to effectively combat this disease. In this study, a series of 14 ethylene glycol analogues of benzothiadiazine-1,1-dioxide were synthesised to investigate their antileishmanial potential and cytotoxicity. Analogue 9, 2-(2-phenoxyethyl)-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide, was identified as the most inhibitory compound as it was observed to moderately inhibit the growth of L. major (IC 50 103 μM) and L. donovani (IC 50 153 μM) promastigotes. However, in general, the series presented with low biological activity, which may be attributed to reduced target affinity and/or undesired cell culture protein binding., (© 2024 The Author(s). Chemistry & Biodiversity published by Wiley-VHCA AG.)