Design, synthesis, electrochemistry and anti-trypanosomatid hit/lead identification of nitrofuranylazines.

Chagas disease and leishmaniasis are vector-borne infectious diseases affecting both humans and animals. These neglected tropical diseases can be fatal if not treated. Hundreds to thousands of new Chagas disease and leishmaniasis cases are being reported by the WHO every year, and currently available treatments are insufficient. Severe adverse effects, impractical administrations and increased pathogen resistance against current clinical treatments underscore a serious need for the development of new drugs to curb these ailments. In search for such drugs, we investigated a series of nitrofuran-based azine derivatives. Herein, we report the design, synthesis, electrochemistry, and biological activity of these derivatives against promastigotes and amastigotes of Leishmania major, and L. donovani strains, as well as epimastigotes and trypomastigotes of Trypanosoma cruzi. Two leishmanicidal early leads and one trypanosomacidal hit with submicromolar activity were uncovered and stand for further in vivo investigation in the search for new antitrypanosomatid drugs. Future objective will focus on the identification of involved biological targets with the parasites.

Exploration of ethylene glycol linked nitrofurantoin derivatives against Leishmania: Synthesis and in vitro activity.

Leishmaniasis is a neglected tropical disease that is caused by the Leishmania parasite. It is estimated that there are more than 350 million people at risk of infection annually. Current treatments that are in clinical use are expensive, have toxic side effects, and are facing parasitic resistance. Therefore, new drugs are urgently required. In the quest for new, safe, and cost-effective drugs, a series of novel ethylene glycol derivatives of nitrofurantoin was synthesised and the in vitro antileishmanial efficacy of the compounds tested against Leishmania donovani and Leishmania major strains. Arylated ethylene glycol derivatives were found to be the most potent, with submicromolar activity up to 294-fold greater than the parent compound nitrofurantoin. Analogues 2j and 2k had the best antipromastigote activities with submicromolar IC50 values against L. major IR-173 and antimonial-resistant L. donovani 9515 strains.

Exploring novel nitrofuranyl sulfonohydrazides as anti-Leishmania and anti-cancer agents: Synthesis, in vitro efficacy and hit identification.

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.

Probing O-substituted nifuroxazide analogues against Leishmania: Synthesis, in vitro efficacy, and hit/lead identification.

Leishmaniasis is a neglected tropical disease affecting millions of people worldwide, with 650 000 to 1.1 million new infections reported annually by the World Health Organization. Current antileishmanial treatments are unsatisfactory due to the development of parasitic resistance and the toxicity associated with the drugs used, and this highlights the need for the development of new antileishmanial drugs. In this study, a series of nifuroxazide analogues were synthesized in a single step reaction and investigated for their antileishmanial potential. The sulfonate 1l, bearing pyridine ring, was deemed an antileishmanial hit, targeting the amastigotes of Leishmania (L.) donovani and L. major, the pathogens of visceral and cutaneous leishmaniasis, respectively, with micromolar potencies. The benzyl analogues 2c and 2d were also confirmed as submicromolar active leads against amastigotes of L. major. These analogues stand as promising candidates for further investigation involving the evaluation of their in vivo activities and molecular targets.

Recent Advances in the Synthesis and Development of Curcumin, its Combinations and Formulations and Curcumin-like Compounds as Anti-infective Agents.

Infectious diseases are caused by pathogenic microorganisms, such as bacteria, fungi, parasites and viruses. Such diseases mostly develop in tropical and sub-tropical climates and represent major health challenges. The pathogens of these diseases are able to multiply in human hosts, warranting their continual survival. Prevention of these diseases is becoming extremely difficult due to the absence of effective vaccines and their treatment, less effective due to the emergence of resistance by their causative pathogens to existing drugs. Several currently available drugs employ oxidative stress, resulting from the generation of reactive oxygen nitrogen species (RONS), as the mechanism for exerting their pharmacological actions. RONS inhibit endogenous antioxidant enzymes, which ultimately eradicate the microbiota. Curcumin, a redox-active natural product, for centuries, has been used in Asian traditional medicine for the treatment of various diseases. It is known for possessing multiple biological and pharmacological activities. Curcumin has been investigated extensively over the years for its anti-inflammatory, anticancer, antiparasitic, antiviral and antibacterial activities, and no toxicity is associated with the compound. Despite its potency and good safety profile, curcumin is still in clinical trials for the treatment of diseases, such as tuberculosis, acquired immunodeficiency syndrome (AIDS), Crohn's disease, colorectal cancer, and multiple myeloma, among many others, as it is yet to be qualified as a therapeutic agent. This review summarizes events over the last decade, especially regarding the discovery of curcumin, an update of its synthesis, its pathogen specific mechanisms of action, and the pharmacological effects of its derivatives, combinations and formulations as potential antibacterial, antifungal, antiparasitic and antiviral agents for the treatment of various infectious diseases.

Synthesis and in vitro antileishmanial efficacy of benzyl analogues of nifuroxazide.

Leishmaniasis is a vector-borne parasitic disease that mostly affects populations in tropical and subtropical countries. There is currently no vaccine to protect against and only a handful of drugs are available to treat this disease. Leishmaniasis is curable, but its eradication and elimination are hindered by the emergence of multidrug resistant strains of the causative pathogens, accentuating the need for new and effective antileishmanial drugs. In search for such agents, nifuroxazide, a clinical antibiotic, was evaluated through investigation of its benzyl analogues for in vitro antileishmanial efficacy against promastigotes of various Leishmania (L.) strains. The monobenzylated analogues 1 and 2 were the most potent of all, possessing nanomolar activities up to 10-fold higher than the parent drug nifuroxazide against all three tested Leishmania strains. Both analogues stand as antipromastigote hits for further lead investigation into their potential to act as new antileishmanial agents.

Recent Advances in the Synthesis and Development of Nitroaromatics as Anti-Infective Drugs.

Infectious diseases commonly occur in tropical and sub-tropical countries. The pathogens of such diseases are able to multiply in human hosts, warranting their continual survival. Infections that are commonplace include malaria, chagas, trypanosomiasis, giardiasis, amoebiasis, toxoplasmosis and leishmaniasis. Malaria is known to cause symptoms, such as high fever, chills, nausea and vomiting, whereas chagas disease causes enlarged lymph glands, muscle pain, swelling and chest pain. People suffering from African trypanosomiasis may experience severe headaches, irritability, extreme fatigue and swollen lymph nodes. As an infectious disease progresses, the human host may also experience personality changes and neurologic problems. If left untreated, most of these diseases can lead to death. Parasites, microbes and bacteria are increasingly adapting and generating strains that are resistant to current clinical drugs. Drug resistance creates an urgency for the development of new drugs to treat these infections. Nitro containing drugs, such as chloramphenicol, metronidazole, tinidazole and secnidazole had been banned for use as antiparasitic agents due to their toxicity. However, recent discoveries of nitrocontaining anti-tuberculosis drugs, i.e. delamanid and pretonamid, and the repurposing of flexinidazole for use in combination with eflornithine for the treatment of human trypanosomiasis, have ignited interest in nitroaromatic scaffolds as viable sources of potential anti-infective agents. This review highlights the differences between old and new nitration methodologies. It furthermore offers insights into recent advances in the development of nitroaromatics as anti-infective drugs.