Design, synthesis and mechanistic exploration of anti-plasmodial Indolo[2,3-]quinoxaline-7-chloroquinoline hybrids.

The aim of this study is to synthesize indolo[2,3-]quinoxaline-4-aminoquinoline-based hybrids and evaluate their effectiveness against chloroquine-susceptible (3D7) and resistant (W2) strains, with expected inhibition of chloroquine resistance transporter (CRT) and heme. The hybrids were synthesized and evaluated against both susceptible and resistant strains. Molecular docking and studies were conducted to assess the binding affinities for the CRT protein.

Design, synthesis and mechanistic insights into triclosan derived dimers as potential anti-plasmodials.

In pursuit of novel anti-plasmodial agents, a library of triclosan-based dimers both with and without a 1-1,2,3 triazole core were designed and synthesized in order to achieve a multitargeted approach. assessment against chloroquine-susceptible (3D7) and resistant (W2) strains identified that two of the synthesized dimers containing triazole were the most potent in the series. The most potent of the synthesized compounds exhibited IC values of 9.

Metal(triphenylphosphine)-atovaquone Complexes: Synthesis, Antimalarial Activity, and Suppression of Heme Detoxification.

To ascertain the bioinorganic chemistry of metals conjugated with quinones, the complexes [Ag(ATV)(PPh)] (), [Au(ATV)(PPh)]·2HO (), and [Cu(ATV)(PPh)] () were synthesized by the coordination of the antimalarial naphthoquinone atovaquone (ATV) to the starting materials [Ag(PPh]NO, [Au(PPh)Cl], and [Cu(PPh)NO], respectively. These complexes were characterized by analytical and spectroscopical techniques. X-ray diffraction of single crystals precisely confirmed the coordination mode of ATV to the metals, which was monodentate or bidentate, depending on the metal center.

Comparison of SD Bioline Malaria Ag Pf/Pan and Acro Malaria P.f./P.v./Pan with Microscopy and Real Time PCR for the Diagnosis of Human Species.

The early diagnosis of malaria is crucial to controlling morbidity and mortality. The World Health Organization (WHO) recommends diagnosing malaria either using light microscopy or a malaria rapid diagnostic test (RDT). Most RDTs use antibodies to detect two histidine-rich proteins named PfHRP2 and PfHRP3.

Long-Read Sequencing and Genome Assembly Pipeline of Two Clones (3D7, W2) Using Only the PromethION Sequencer from Oxford Nanopore Technologies without Whole-Genome Amplification.

Antimalarial drug resistance has become a real public health problem despite WHO measures. New sequencing technologies make it possible to investigate genomic variations associated with resistant phenotypes at the genome-wide scale. Based on the use of hemisynthetic nanopores, the PromethION technology from Oxford Nanopore Technologies can produce long-read sequences, in contrast to previous short-read technologies used as the gold standard to sequence Plasmodium.

Comparative Assessment of the Sensitivity of Ten Commercial Rapid Diagnostic Test Kits for the Detection of .

Malaria is one of the most common tropical diseases encountered by members of the French military who are deployed in operations under constrained conditions in malaria-endemic areas. Blood smear microscopy-the gold standard for malaria diagnosis-is often not available in such settings, where the detection of malaria relies on rapid diagnostic tests (RDTs). Ten RDTs (from Biosynex, Carestart, Humasis, SD Bioline, and CTK Biotech), based on the detection of the histidine-rich protein 2 (HRP2) or lactate dehydrogenase (pLDH, PfLDH, or PvLDH), were assessed against 159 samples collected from imported malaria cases, including 79 , 37 , 22 , and 21 parasites.

Synthesis, Anti-Plasmodial Activities, and Mechanistic Insights of 4-Aminoquinoline-Triazolopyrimidine Hybrids.

In the search of new antiplasmodial agents, a multitargeted approach was used in the synthesis of triazolopyrimidine- and 4-aminoquinolines-based hybrids. antiplasmodial evaluation on chloroquine-sensitive (3D7) and -resistant (W2) strains identified triazolopyrimidine-4-aminoquinoline hybrids to be the most potent in the series, outperforming bis-triazolopyrimidines. The active compounds were subjected to mechanistic studies with the plausible and expected targets including heme, PfCRT, and PfDHODH, that eventually validated the biological data.

A Hybrid of Amodiaquine and Primaquine Linked by Gold(I) Is a Multistage Antimalarial Agent Targeting Heme Detoxification and Thiol Redox Homeostasis.

Hybrid-based drugs linked through a transition metal constitute an emerging concept for intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF. This compound demonstrated potent and efficacious antiplasmodial activity against multiple stages of the life cycle.

Repurposing of Doxycycline to Hinder the Viral Replication of SARS-CoV-2: From to Validation.

Since the rapid spread of coronavirus disease (COVID-19) became a global pandemic, healthcare ministries around the world have recommended specific control methods such as quarantining infected peoples, identifying infections, wearing mask, and practicing hand hygiene. Since no effective treatment for COVID-19 has yet been discovered, a variety of drugs approved by Food and Drug Administration (FDA) have been suggested for repurposing strategy. In the current study, we predicted that doxycycline could interact with the nucleotide triphosphate (NTP) entry channel, and is therefore expected to hinder the viral replication of SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp) through docking analysis.

Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants.

Over the past two years, several variants of SARS-CoV-2 have emerged and spread all over the world. However, infectivity, clinical severity, re-infection, virulence, transmissibility, vaccine responses and escape, and epidemiological aspects have differed between SARS-CoV-2 variants. Currently, very few treatments are recommended against SARS-CoV-2.

Prevalence of Mutations in the Gene and Association with Ex Vivo Susceptibility to Common Quinoline Drugs against .

Background: Artemisinin-based combination therapy (ACT) was recommended to treat uncomplicated falciparum malaria. Unlike the situation in Asia where resistance to ACT has been reported, artemisinin resistance has not yet emerged in Africa. However, some rare failures with ACT or patients continuing to be parasitaemic on day 3 after ACT treatment have been reported in Africa or in travellers returning from Africa.

In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2.

A new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19), which emerged in Wuhan, China in December 2019, has spread worldwide. Currently, very few treatments are officially recommended against SARS-CoV-2. Identifying effective, low-cost antiviral drugs with limited side effects that are affordable immediately is urgently needed.

Absence of Association between Methylene Blue Reduced Susceptibility and Polymorphisms in 12 Genes Involved in Antimalarial Drug Resistance in African .

Half the human population is exposed to malaria. antimalarial drug resistance monitoring and development of new drugs are major issues related to the control of malaria. Methylene blue (MB), the oldest synthetic antimalarial, is again a promising drug after the break of its use as an antimalarial drug for more than 80 years and a potential partner for triple combination.

Synthesis and antiplasmodial evaluation of 1H-1,2,3-triazole grafted 4-aminoquinoline-benzoxaborole hybrids and benzoxaborole analogues.

A library of 1H-1,2,3-triazole-tethered 4-aminoquinoline-benzoxaborole hybrids as well as aryl substituted benzoxaborole analogues was synthesized and screened for their anti-plasmodial efficacy against both chloroquine-susceptibility 3D7 and chloroquine-resistant W2 strains of P. falciparum. The inclusion of quinoline core among the synthesized analogues resulted in substantial enhancement of anti-plasmodial activities.

Amide Tethered 4-Aminoquinoline-naphthalimide Hybrids: A New Class of Possible Dual Function Antiplasmodials.

A series of amide tethered 4-aminoquinoline-naphthalimide hybrids has been synthesized to assess their in vitro antiplasmodial potential against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of . The most active and noncytotoxic compound had an IC value of 0.07 μM against W2 strain and was more active than standard antimalarial drugs, including chloroquine, desethylamodiaquine, and quinine, particularly for drug resistant malaria.

A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent.

Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages.

Methylene blue inhibits replication of SARS-CoV-2 in vitro.

In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. Currently there is no antiviral treatment recommended against SARS-CoV-2. Identifying effective antiviral drugs is urgently required.

Absence of association between polymorphisms in the pfcoronin and pfk13 genes and the presence of Plasmodium falciparum parasites after treatment with artemisinin derivatives in Senegal.

Due to resistance to chloroquine and sulfadoxine/pyrimethamine, treatment for uncomplicated Plasmodium falciparum malaria switched to artemisinin-based combination therapy (ACT) in 2006 in Senegal. Several mutations in the gene encoding the kelch13 helix (pfk13-propeller) have been identified as associated with in vitro and in vivo artemisinin resistance in Southeast Asia. Additionally, three mutations in the pfcoronin gene (G50E, R100K and E107V) have been identified in two culture-adapted Senegalese field isolates that became resistant in vitro to artemisinin after 4 years of intermittent selection with dihydroartemisinin.

Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation.

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. African countries see slower dynamic of COVID-19 cases and deaths. One of the assumptions that may explain this later emergence in Africa, and more particularly in malaria endemic areas, would be the use of antimalarial drugs.

Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: In vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate.

Objectives: At the end of November 2019, a novel coronavirus responsible for respiratory tract infections (COVID-19) emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with a particular hotspot in Southern Europe and America; many studies predicted a similar epidemic in Africa, as is currently seen in Europe and the United States of America.

Prevalence of mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, and association with ex vivo susceptibility to common anti-malarial drugs against African Plasmodium falciparum isolates.

Background: The Plasmodium falciparum chloroquine transporter gene (pfcrt) is known to be involved in chloroquine and amodiaquine resistance, and more particularly the mutations on the loci 72 to 76 localized within the second exon. Additionally, new mutations (T93S, H97Y, C101F, F145I, M343L, C350R and G353V) were recently shown to be associated with in vitro reduced susceptibility to piperaquine in Asian or South American P. falciparum strains.

Baseline and multinormal distribution of ex vivo susceptibilities of Plasmodium falciparum to methylene blue in Africa, 2013-18.

Background: Plasmodium falciparum resistance to most antimalarial compounds has emerged in Southeast Asia and spread to Africa. In this context, the development of new antimalarial drugs is urgent.

Objectives: To determine the baseline in vitro activity of methylene blue (Proveblue®) on African isolates and to determine whether parasites have different phenotypes of susceptibility to methylene blue.