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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 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. [ABSTRACT FROM AUTHOR]

Currently available drugs being used to treat leishmaniasis have several shortcomings, including high toxicity, drug administration that requires hospitalization, and the emergence of parasite resistance against clinically used drugs. As a result, there is a dire need for the development of new antileishmanial drugs that are safe, affordable, and efficient. In this study, two new series of synthesized quinazolinone derivatives were investigated as potential future antileishmanial agents, by assessing their activities against the Leishmania (L.) donovani and L. major species. The cytotoxicity profiles of these derivatives were assessed in vitro on Vero cells. The compounds were found to be safer and without any toxic activities against mammalian cells, compared to the reference drug, halofuginone, a clinical derivative of febrifugine. However, they had demonstrated poor antileishmanial growth inhibition efficacies. The two compounds that had been found the most active were the mono quinazolinone 2d and the bisquinazolinone 5b with growth inhibitory efficacies of 35% and 29% for the L. major and L. donovani 9515 promastigotes, respectively. These outcomes had suggested structural redesign, inter alia the inclusion of polar groups on the quinazolinone ring, to potentially generate novel quinazolinone derivatives, endowed with effective antileishmanial potential. [ABSTRACT FROM AUTHOR]

Tuberculosis is the deadliest infectious disease affecting humankind with a death toll of approximately 1.7 million people in 2016. The increasing prevalence of multidrug‐resistant strains of the causative pathogen, Mycobacterium tuberculosis (Mtb) which results in reduced effectiveness of the current therapies, underscores the urgent need for the development of new antitubercular drugs. In the search for such drugs, we investigated two series of ciprofloxacin (CPX) derivatives (analogues and hybrids). We herein report the design, synthesis, and biological activity of these series against the human virulent Mtb H37Rv strain in vitro. The small propionyl analogue 11 (MIC90 1.6 μM; SI > 61) and the large cholesteryl hybrid 32 (MIC90 2.0 μM; SI > 6) were the most active derivatives, comparable to CPX (MIC90 1.8 μM). However, the slightly less active but non‐cytotoxic para‐fluorobenzyl hybrid 28 (MIC90 3.7 μM; SI 27) was more selective toward bacteria than 32. Thus, the CPX derivatives 11 and 28 were identified as preferred antitubercular hits for further investigation including distribution, metabolism and pharmacokinetic parameters determination and in vivo activity assessment in animal models. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a vector-borne parasitic disease that mostly affects populations in tropical and sub-tropical countries. There is currently no protective anti-leishmanial vaccine and only a paucity of clinical drugs is available to treat this disease albeit their toxicity. Leishmaniasis is curable but its eradication and elimination have been hampered by the emergence of multidrug resistant strains of the causative pathogens. This heightens the necessity for new and effective antileishmanial drugs. In search for such agents, nitrofurantoin, a clinical antibiotic, was appended to triazole scaffold through alkylene linkers of various length, and the resulting hybrids were evaluated for in vitro antileishmanial efficacy against Leishmania (L.) parasite of two strains. The hybrid 13 , harboring a n -pentylene linker was uncovered as a leishmanicidal hit with micromolar activity against antimonial-resistant L. donovani , the causative of deadly visceral Leishmaniasis. [Display omitted] • A series of 28 nitrofurantoin-triazole hybrids were synthesized via Click chemistry. • In vitro antileishmanial activity was tested using L. major and L. donovani strains. • Several antileishmanial hits with micromolar activity were uncovered. • Hybrid 13 was identified as leishmanicidal against L. donovani amastigote. [ABSTRACT FROM AUTHOR]

Objectives (i) To optimize cell-free DNA (cfDNA) and mRNA quantification using eight housekeeping genes (HKGs), (ii) to determine if there is a difference in the occurrence of HKGs in the cfDNA and mRNA of normal cells and cancer cells, and (iii) to investigate whether there is some selectivity involved in the release of cfDNA. Design and methods cfDNA was isolated directly from the growth medium of 3 cultured cancer cell lines and one non-malignant, primary cell line. At the same time interval, mRNA was isolated from these cells and cDNA was synthesized. CfDNA and cDNA were then amplified with real-time PCR utilizing eight different HKGs. Results For all cell lines tested, Beta-actin (ACTB) is the most appropriate HKG to use as a control for cfDNA and mRNA quantification. There was no clear difference in the occurrence of HKGs between cancer cells and healthy cells. Lastly, there is a consistent and distinct difference between the mRNA expression and cfDNA of all cell lines. Conclusions This study reveals a new candidate HKG for a robust control in cfDNA analysis and gene expression profiling, and should be considered for optimal analysis. Furthermore, results indicate that cfDNA is selectively released from cells into culture medium. [ABSTRACT FROM AUTHOR]

Significant overlaps in the geographical distribution of malaria and leishmaniasis increase the risk for comorbidity, which can affect treatment efficacy, cotreatment compatibility and disease progression. These concerns are also exacerbated by the existing shortcomings of malaria and leishmaniasis treatments. There is, therefore, a pressing need for new anti-infective drugs for both individual diseases and coinfections. The in vitro antileishmanial activity of previously synthesized antiplasmodial aminoquinoline-chalcone hybrids was evaluated. Hybrid 6 , featuring a N-methyl-1,3-propylene diamine linker between pharmacophores, was 11-fold more potent in anti-amastigote activity against Leishmania major , responsible for cutaneous leishmaniasis, the most common form of the disease, in comparison to chloroquine. Hybrid 7 , with a 2,2-(ethylenedioxy)bis(ethylamine) linker, was nearly 7-fold more active in anti-amastigote activity against Leishmania donovani , responsible for visceral leishmaniasis, the most lethal form of the infection. Although these two hybrids were less potent than the clinically used antileishmanial, amphotericin B, they still qualify as hits against both Plasmodium and Leishmania strains. Accordingly, this may lend them as potential agents against Leishmania-Plasmodium coinfections, which will require further investigation using in vitro co-cultures and subsequent in vivo testing for confirmation. [Display omitted] • New drugs for malaria, leishmaniasis and coinfections are urgently required. • In vitro antileishmanial activity of anti-malarial quinoline-chalcones was tested. • Hybrids 6 and 7 are in vitro hits against visceral and cutaneous parasite strains. • These hybrids are drug-like with micromolar in vitro antileishmanial properties. [ABSTRACT FROM AUTHOR]

• Antiplasmodial active artemisinins screened against various Leishmania strains. • Several antipromastigote hits. • Leishmania were less susceptible to artemisinin derivatives than Plasmodia. • Promising anti-coinfection hits. Leishmaniasis is a neglected tropical disease affecting thousands worldwide, especially in developing countries where it co-exists with malaria. Only a handful of drugs are clinically available to treat the disease, but significant limitations threaten their very use. New, safe and effective drugs, including those against malaria-leishmaniasis co-infections, are thus imperative. We assessed the in vitro anti-infective potential of previously synthesized, potent antimalarial artemisinin derivatives. Analogue esters featuring 1,1′-biphenyl and thiophenyl moieties were as much as 30-fold more potent than clinical artemisinins against L. donovani parasites, qualifying them as antipromastigote hits for further investigation in the search for malaria-leishmaniasis co-infection therapies. [ABSTRACT FROM AUTHOR]

The true importance of cell-free DNA in human biology, together with the potential scale of its clinical utility, is tarnished by a lack of understanding of its composition and origin. In investigating the cell-free DNA present in the growth medium of cultured 143B cells, we previously demonstrated that the majority of cell-free DNA is neither a product of apoptosis nor necrosis. In the present study, we investigated the composition and origin of this cell-free DNA population using next-generation sequencing. We found that the cell-free DNA comprises mainly of repetitive DNA, including α-satellite DNA, mini satellites, and transposons that are currently active or exhibit the capacity to become reactivated. A significant portion of these cell-free DNA fragments originates from specific chromosomes, especially chromosomes 1 and 9. In healthy adult somatic cells, the centromeric and pericentromeric regions of these chromosomes are normally densely methylated. However, in many cancer types, these regions are preferentially hypomethylated. This can lead to double-stranded DNA breaks or it can directly impair the formation of proper kinetochore structures. This type of chromosomal instability is a precursor to the formation of nuclear anomalies, including lagging chromosomes and anaphase bridges. DNA fragments derived from these structures can recruit their own nuclear envelope and form secondary nuclear structures known as micronuclei, which can localize to the nuclear periphery and bud out from the membrane. We postulate that the majority of cell-free DNA present in the growth medium of cultured 143B cells originates from these micronuclei. [ABSTRACT FROM AUTHOR]