New antimalarial iromycin analogs produced by Streptomyces sp. RBL-0292.

Two new antimalarial compounds, named prenylpyridones A (1) and B (2), were discovered from the actinomycete cultured material of Streptomyces sp. RBL-0292 isolated from the soil on Hamahiga Island in Okinawa prefecture. The structures of 1 and 2 were elucidated as new iromycin analogs having α-pyridone ring by MS and NMR analyses. Compounds 1 and 2 showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 80.7 to 106.7 µM.

SARS-CoV-2 Contamination on Healthy Individuals' Hands in Community Settings During the COVID-19 Pandemic.

Introduction Hand hygiene is an infection control measure for COVID-19 in our daily lives; however, the contamination levels of SARS-CoV-2 in the hands of healthy individuals remain unclear. Thus, we aimed to evaluate SARS-CoV-2 contamination levels by detecting viral RNA and viable viruses in samples obtained from the hands of 925 healthy individuals. Methods Swab samples were collected from the palms and fingers of healthy participants, including office workers, public officers, university students, university faculty and staff, and hospital staff between December 2022 and March 2023. The collected swab samples were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for SARS-CoV-2 RNA detection. Viral RNA-positive samples were subjected to plaque assay to detect viable viruses. Results We collected 1,022 swab samples from the hands of healthy participants. According to the criteria for data collection, 97 samples were excluded, and 925 samples were analyzed using RT-qPCR. SARS-CoV-2 RNA was detected in three of the 925 samples. The viral RNA detection rate was 0.32% (3/925), and the viral RNA copy numbers ranged from 5.0×103 to 1.7×105 copies/mL. The RT-qPCR-positive samples did not contain viable viruses, as confirmed by the plaque assay results. Conclusions The detection rate of SARS-CoV-2 RNA from the hands of healthy individuals was extremely low, and no viable viruses were detected. These results suggest that the risk of contact transmission via hands in a community setting is extremely rare.

Akedanones A-C, In Vitro and In Vivo Antiplasmodial 2,3-Dihydronaphthoquinones Produced by Streptomyces sp. K20-0187.

Three new antiplasmodial compounds, named akedanones A (1), B (2), and C (3), were discovered from the cultured material of Streptomyces sp. K20-0187 isolated from a soil sample collected at Takeda, Kofu, Yamanashi prefecture in Japan. The structures of compounds 1-3 were elucidated as new 2,3-dihydronaphthoquinones having prenyl and reverse prenyl groups by mass spectrometry and nuclear magnetic resonance analyses. Compound 1 and the known furanonaphthoquinone I (4) showed potent in vitro antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with half-maximal inhibitory concentration values ranging from 0.06 to 0.3 µM. Compounds 1 and 4 also displayed potent in vivo antiplasmodial activity against drug-sensitive rodent malaria Plasmodium berghei N strain, with inhibition rates of 47.6 and 43.1%, respectively, on intraperitoneal administration at a dose of 5 mg kg-1 day-1 for 4 days.

Virgaricins C and D, new pramanicin analogs produced by Apiospora sp. FKI-8058.

Two new pramanicin analogs, named virgaricins C (1) and D (2), were discovered by physicochemical screening from a static cultured material of Apiospora sp. FKI-8058. Their structures were elucidated by MS and NMR analyses and chemical derivatization. Compounds 1 and 2 showed moderate antimalarial activity and cytotoxicity.

A novel aromatic compound from the fungus Synnemellisia sp. FKR-0921.

The filamentous fungus Synnemellisia sp. strain FKR-0921 was obtained from soil collected on Kume Island, Okinawa. The MeOH extract of FKR-0921 cultured on a solid rice medium yielded a new aromatic compound, synnemellisitriol A (1). The structure, including the absolute configuration, was elucidated by spectroscopic analysis (FT-IR, NMR, and HR-ESI-MS), and the absolute configuration at C-9 of 1 was determined using the modified Mosher's method. Additionally, 1 was evaluated for its biological activities, including metallo-ß-lactamase inhibitory activity, type III secretion system inhibitory activity, antimicrobial activity, antimalarial activity, and cytotoxicity.

New antimalarial fusarochromanone analogs produced by the fungal strain Fusarium sp. FKI-9521.

Two new antimalarial compounds, named deacetyl fusarochromene (1) and 4'-O-acetyl fusarochromanone (2), were discovered from the static fungal cultured material of Fusarium sp. FKI-9521 isolated from feces of a stick insect (Ramulus mikado) together with three known compounds fusarochromanone (3), 3'-N-acetyl fusarochromanone (4), and 5 (fusarochromene or banchromene). The structures of 1 and 2 were elucidated as new analogs of 3 by MS and NMR analyses. The absolute configurations of 1, 2, and 4 were determined by chemical derivatization. All five compounds showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 0.08 to 6.35 µM.

Assessment of environmental surface contamination with SARS-CoV-2 in concert halls and banquet rooms in Japan.

BACKGROUND: Although crowds are considered to be a risk factor for SARS-CoV-2 transmission, little is known about the changes in environmental surface contamination with the virus when a large number of people attend an event. In this study, we evaluated the changes in environmental surface contamination with SARS-CoV-2. METHODS: Environmental samples were collected from concert halls and banquet rooms before and after events in February to April 2022 when the 7-day moving average of new COVID-19 cases in Tokyo was reported to be 5000-18000 cases per day. In total, 632 samples were examined for SARS-CoV-2 by quantitative reverse transcription polymerase chain reaction (RT-qPCR) tests, and RT-qPCR-positive samples were subjected to a plaque assay. RESULTS: The SARS-CoV-2 RNA detection rate before and after the events ranged from 0% to 2.6% versus 0%-5.0% in environmental surface samples, respectively. However, no viable viruses were isolated from all RT-qPCR-positive samples by the plaque assay. There was no significant increase in the environmental surface contamination with SARS-CoV-2 after these events. CONCLUSIONS: These findings revealed that indirect contact transmission from environmental fomite does not seem to be of great magnitude in a community setting.

Koshidacins A and B, Antiplasmodial Cyclic Tetrapeptides from the Okinawan Fungus Pochonia boninensis FKR-0564.

Two new antiplasmodial peptides, named koshidacins A (1) and B (2), were discovered from the culture broth of the Okinawan fungus Pochonia boninensis FKR-0564. Their structures, including absolute configurations, were elucidated by a combination of spectroscopic methods and chemical derivatization. Both compounds showed moderate in vitro antiplasmodial activity against Plasmodium falciparum strains, with IC50 values ranging from 17.1 to 0.83 µM. In addition, compound 2 suppressed 41% of malaria parasites in vivo when administered intraperitoneally at a dose of 30 mg/kg/day for 4 days.

Semisynthesis of Antitrypanosomal p-Quinone Analog Possesing the Komaroviquinone Pharmacophore.

A p-quinone analog having the komaroviquinone pharmacophore fused with a more conformationally flexible cycloheptane ring, was semisynthesized from natural demethlsalvicanol isolated from Perovskia abrotanoides via four steps in 26% overall yield. The IC50 for the antitrypanosomal activity of the analog was 0.55 µM.

Shikinefragalides A-D, new tricyclic macrolides produced by Stachybotryaceae sp. FKI-9632.

Four new tricyclic macrolides, named shikinefragalides A (1), B (2), C (3) and D (4), were isolated by physicochemical (PC) screening from a static culture material of Stachybotryaceae sp. FKI-9632. Their structures were elucidated as new analogs of colletofragarones by MS and NMR analyses. Compounds 1 and 2 showed weak antimalarial activity and cytotoxicity.

Discoveries and Syntheses of Highly Potent Antimalarial Troponoids.

Novel derivatives of puberulic acid were synthesized and their antimalarial properties were evaluated in vitro against the Plasmodium falciparum K1 parasite strain, cytotoxicity against a human diploid embryonic cell line MRC-5, and in vivo efficacy using a Plasmodium berghei-infected mouse model. From previous information that three hydroxy groups on the tropone framework were essential for antimalarial activity, we converted the carboxylic acid moiety into the corresponding esters, amides, and ketones. These derivatives showed antimalarial activity against chloroquine-resistant Plasmodium in vitro equivalent to puberulic acid. We identified that the pentane-3-yl ester, cyclohexyl ester, iso-butyl ketone, cyclohexyl methyl ketone all show an especially potent antiparasitic effect in vivo at an oral dose of 15 mg/kg without any apparent toxicity. These esters were more effective than the existing commonly used antimalarial drug, artesunate.

Diatretol, an α, α'-dioxo-diketopiperazine, is a potent in vitro and in vivo antimalarial.

A fungal metabolite, diatretol, has shown to be a promising antimalarial agent. Diatretol displayed potent in vitro antiparasitic activity against the Plasmodium falciparum K1 strain, with an IC50 value of 378 ng ml-1, as well as in vivo efficacy in a Plasmodium berghei-infected mice model, with ca. 50% inhibition at 30 mg/kg (p.o.).

A Concise Total Synthesis of Dehydroantofine and Its Antimalarial Activity against Chloroquine-Resistant Plasmodium falciparum.

The total synthesis of dehydroantofine was achieved by employing a novel, regioselective, azahetero Diels-Alder reaction of easily accessible 3,5-dichloro-2H-1,4-oxazin-2-one with 14 a as a key step. Furthermore, it is demonstrated that dehydroantofine is a promising candidate as a new antimalarial agent in a biological assay with chloroquine-resistant Plasmodium falciparum.

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents.

BACKGROUND: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. OBJECTIVE: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3- cinnamamido-N-substituted benzamides. METHODS: In this study, a screening of our compound library was carried out against the multidrugsensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters' 4-day suppressive test. RESULTS: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective, which might be ascribed to the poor solubility of these compounds. CONCLUSION: In this study, the phenotypic screen of our compound library resulted in the first report of a 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against the P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

Hatsusamides A and B: Two New Metabolites Produced by the Deep-Sea-Derived Fungal Strain Penicillium steckii FKJ-0213.

Two new nitrogen-containing metabolites, designated hatsusamide A (1) and B (2), were isolated from a culture broth of Penicilliumsteckii FKJ-0213 together with the known compounds tanzawaic acid B (3) and trichodermamide C (4) by physicochemical (PC) screening. The structures of 1 and 2 were determined as a tanzawaic acid B-trichodermamide C hybrid structure and a new analog of aspergillazines, respectively. The absolute configuration of 1 was determined by comparing the values of tanzawaic acid B and trichodermamide C in the literatures, such as 1H-nuclear magnetic resonance (1H-NMR) data and optical rotation, after hydrolysis of 1. Compounds 1-4 were evaluated for cytotoxicity and anti-malarial activities. Compounds 1 and 3 exhibited weak anti-malarial activity at half-maximal inhibitory concentration (IC50) values of 27.2 and 78.5 µM against the K1 strain, and 27.9 and 79.2 µM against the FCR3 strain of Plasmodium falciparum, respectively. Furthermore, 1 exhibited cytotoxicity against HeLa S3, A549, Panc1, HT29 and H1299 cells, with IC50 values of 15.0, 13.7, 12.9, 6.8, and 18.7 µM, respectively.

Rapid and Systematic Exploration of Chemical Space Relevant to Artemisinins: Anti-malarial Activities of Skeletally Diversified Tetracyclic Peroxides and 6-Aza-artemisinins.

To achieve both structural changes and rapid synthesis of the tetracyclic scaffold relevant to artemisinins, we explored two kinds of de novo synthetic approaches that generate both skeletally diversified tetracyclic peroxides and 6-aza-artemisinins. The anti-malarial activities of the tetracyclic peroxides with distinct skeletal arrays, however, were moderate and far inferior to artemisinins. Given the privileged scaffold of artemisinins, we next envisioned element implantation at the C6 position with a nitrogen without the trimmings of substituents and functional groups. This molecular design allowed the deep-seated structural modification of the hitherto unexplored cyclohexane moiety (C-ring) while keeping the three-dimensional structure of artemisinins. Notably, this approach induced dramatic changes of retrosynthetic transforms that allow an expeditious catalytic asymmetric synthesis with generation of substitutional variations at three sites (N6, C9, and C3) of the 6-aza-artemisinins. These de novo synthetic approaches led to the lead discovery with substantial intensification of the in vivo activities, which undermine the prevailing notion that the C-ring of artemisinins appears to be merely a structural unit but to be a functional area as the anti-malarial pharmacophore. Furthermore, we unexpectedly found that racemic 6-aza-artemisinin (33) exerted exceedingly potent in vivo efficacies superior to the chiral one and the first-line drug, artesunate.

Structure-Activity Relationship between Thiol Group-Trapping Ability of Morphinan Compounds with a Michael Acceptor and Anti-Plasmodium falciparum Activities.

7-Benzylidenenaltrexone (BNTX) and most of its derivatives showed in vitro antimalarial activities against chloroquine-resistant and -sensitive Plasmodium falciparum strains (K1 and FCR3, respectively). In addition, the time-dependent changes of the addition reactions of the BNTX derivatives with 1-propanethiol were examined by 1H-NMR experiments to estimate their thiol group-trapping ability. The relative chemical reactivity of the BNTX derivatives to trap the thiol group of 1-propanethiol was correlated highly with the antimalarial activity. Therefore, the measurements of the thiol group-trapping ability of the BNTX derivatives with a Michael acceptor is expected to become an alternative method for in vitro malarial activity and related assays.

Clonocoprogens A, B and C, new antimalarial coprogens from the Okinawan fungus Clonostachys compactiuscula FKR-0021.

Three new antimalarial compounds, clonocoprogens A, B, and C, were isolated from the static culture of an Okinawan fungus, Clonostachys compactiuscula FKR-0021. These compounds were new analogs of N14-palmitoylcoprogen, reported as a siderophore. They showed moderate antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 1.7 to 9.9 µM.

Kozupeptins, Antimalarial Agents Produced by Paracamarosporium Species: Isolation, Structural Elucidation, Total Synthesis, and Bioactivity.

Kozupeptins A and B, novel antimalarial lipopeptides, were isolated from the culture broths of Paracamarosporium sp. FKI-7019. They exhibited potent antimalarial activity against chloroquine-sensitive and -resistant Plasmodium falciparum strains in vitro. The structural elucidation was accomplished by a combination of spectroscopic analyses and chemical approaches including a total synthesis of kozupeptin A. Synthetic kozupeptin A demonstrated a therapeutic effect in vivo, and an intermediate exhibited much higher antimalarial activity than kozupeptin A.

Peyer's patch-immunomodulating glucans from sugar cane enhance protective immunity through stimulation of the hemopoietic system.

The aim of the present study was chemical clarification of in vitro Peyer's patch-immunomodulating polysaccharides in sugar cane molasses, and evaluation of in vivo modulating activity on immune function of T lymphocytes in Peyer's patches and on microenvironment of hemopoietic system. Five kinds of glucans, comprising of dextranase-sensitive and activity-related d-glucosyl moieties, were purified as in vitro Peyer's patch-immunomodulating polysaccharides from the molasses. Oral administration of a glucan-enriched subfraction induced IL-2 and GM-CSF-producing T lymphocytes in Peyer's patches, resulting in enhancement of IL-6 production in a hemopoietic microenvironment to boost neutrophil numbers in the peripheral blood stream. Oral administration of purified glucan or glucan-enrich sub-fraction of sugar cane reduced the number of Plasmodium berghei- or P. yoelii-infected erythrocytes in a murine infection model, using polysaccharide alone or via co-administration with the antimalarial drug, artesunate. These results suggested that Peyer's patch-immunomodulating glucans enhanced protective immunity through axis of Peyer's patches-hemopoietic system.