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A two-step formal (4 + 1) annulation-dehydration reaction offers a convenient route to C2-arylated indoles and benzofurans. This reaction exploits the bifunctional reactivity of electron-deficient benzyl chlorides with N -sulfonyl-2-aminobenzaldehydes or salicylaldehyde derivatives. The reaction tolerates both electron-withdrawing and donating groups on the substituted aldehydes, as well as variation of electron-withdrawing groups at the para position of the benzyl chloride reagent. This work also identifies interesting byproducts resulting from the self-reaction of these benzyl chlorides under basic conditions.

A G4C2 hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Bidirectional transcription and subsequent repeat-associated non-AUG (RAN) translation of sense and antisense transcripts leads to the formation of five dipeptide repeat (DPR) proteins. These DPRs are toxic in a wide range of cell and animal models. Therefore, decreasing RAN-DPRs may be of therapeutic benefit in the context of C9ALS/FTD. In this study, we found that C9ALS/FTD patients have reduced expression of the AAA+ family members RuvBL1 and RuvBL2, which have both been implicated in aggregate clearance. We report that overexpression of RuvBL1, but to a greater extent RuvBL2, reduced C9orf72-associated DPRs in a range of in vitro systems including cell lines, primary neurons from the C9-500 transgenic mouse model, and patient-derived iPSC motor neurons. In vivo, we further demonstrated that RuvBL2 overexpression and consequent DPR reduction in our Drosophila model was sufficient to rescue a number of DPR-related motor phenotypes. Thus, modulating RuvBL levels to reduce DPRs may be of therapeutic potential in C9ALS/FTD., (© 2024 Webster et al.)

To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.g., 1 96 h IC 50 550 nM; 3 96 h IC 50 160 nM) with a different action to delayed-death slow-action drugs. A series of analogues were synthesized from thiotetrazoles and carbomoyl derivatives using Huisgen 1,3,4-oxadiazole synthesis followed by oxidation of the resultant thioethers to target sulfones. Structure activity relationship analysis of analogues identified compounds with potent and selective in vitro activity against drug-sensitive and multi-drug resistant Plasmodium parasites (e.g., 31 and 32 96 h IC 50 <40 nM; SI > 2500). Subsequent studies in mice with compound 1, which had the best microsomal stability of the compounds assessed (T 1/2 >255 min), demonstrated rapid clearance and poor oral in vivo efficacy in a P. berghei murine malaria model. These data indicate that while N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines are a novel class of slow-acting antiplasmodial agents, the further development of this chemotype for malaria chemoprophylaxis will require pharmacokinetic profile improvements., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katherine Andrews, Tina Skinner-Adams, Oliver Hutt, John Ryan, Andrew Riches reports financial support was provided by National Health and Medical Research Council of Australia. Anjana Rai reports financial support was provided by Griffith University GUIPRS and GUPRS PhD scholarships. Katherine Andrews reports equipment, drugs, or supplies was provided by Australian Red Cross Lifeblood. Katherine Andrews reports writing assistance was provided by Monash Institute of Pharmaceutical Sciences Centre for Drug Candidate Optimisation. Katherine Andrews reports equipment, drugs, or supplies was provided by Compounds Australia, Griffith University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals. However, despite this impact, there is no vaccine for Giardia currently available. In addition, treatment relies on chemotherapies that are associated with increasing failure rates. To identify new treatment options for giardiasis we recently screened the Compounds Australia Scaffold Library for new chemotypes with selective anti-Giardia activity, identifying three compounds with sub-μM activity and promising selectivity. Here we extended these studies by examining the anti-Giardia activity of series CL9569 compounds. This compound series was of interest given the promising activity (IC 50 1.2 μM) and selectivity demonstrated by representative compound, SN00798525 (1). Data from this work has identified an additional three thieno [3,2-b]pyrrole 5-carboxamides with anti-Giardia activity, including 2 which displayed potent cytocidal (IC 50  ≤ 10 nM) and selective activity against multiple Giardia strains, including representatives from both human-infecting assemblages and metronidazole resistant parasites. Preclinical studies in mice also demonstrated that 2 is well-tolerated, does not impact the normal gut microbiota and can reduce Giardia parasite burden in these animals., Competing Interests: Declarations of competing interest CJS Hart, AG Riches, JH Ryan, and TS Skinner-Adams, are inventors on a PCT application that covers small molecule compounds derived from the compounds discussed in this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Contraceptive choice is central to reproductive autonomy. The internet, including social networking sites like Reddit, is an important resource for people seeking contraceptive information and support. A subreddit dedicated to contraception, r/birthcontrol, provides a platform for people to post about contraception., Objective: This study explored the use of r/birthcontrol, from the inception of the subreddit through the end of 2020. We describe the web-based community, identify distinctive interests and themes based upon the textual content of posts, and explore the content of posts with the most user engagement (ie, "popular" posts)., Methods: Data were obtained from the PushShift Reddit application programming interface from the establishment of r/birthcontrol to the start date of analysis (July 21, 2011, to December 31, 2020). User interactions within the subreddit were analyzed to describe community use over time, specifically the commonality of use based on the volume of posts, the length of posts (character count), and the proportion of posts with any and each flair applied. "Popular" posts on r/birthcontrol were determined based on the number of comments and "scores," or upvotes minus downvotes; popular posts had 9 comments and a score of ≥3. Term Frequency-Inverse Document Frequency (TF-IDF) analyses were run on all posts with flairs applied, posts within each flair group, and popular posts within each flair group to characterize and compare the distinctive language used in each group., Results: There were 105,485 posts to r/birthcontrol during the study period, with the volume of posts increasing over time. Within the time frame for which flairs were available on r/birthcontrol (after February 4, 2016), users applied flairs to 78% (n=73,426) of posts. Most posts contained exclusively textual content (n=66,071, 96%), had comments (n=59,189, 86%), and had a score (n=66,071, 96%). Posts averaged 731 characters in length (median 555). "SideEffects!?" was the most frequently used flair overall (n=27,530, 40%), while "Experience" (n=719, 31%) and "SideEffects!?" (n=672, 29%) were most common among popular posts. TF-IDF analyses of all posts showed interest in contraceptive methods, menstrual experiences, timing, feelings, and unprotected sex. While TF-IDF results for posts with each flair varied, the contraceptive pill, menstrual experiences, and timing were discussed across flair groups. Among popular posts, intrauterine devices and contraceptive use experiences were often discussed., Conclusions: People commonly wrote about contraceptive side effects and experiences using methods, highlighting the value of r/birthcontrol as a space to post about aspects of contraceptive use that are not well addressed by clinical contraceptive counseling. The value of real-time, open-access data on contraceptive users' interests is especially high given the shifting landscape of and increasing constraints on reproductive health care in the United States., (©Elizabeth Pleasants, Julia Holmes Ryan, Cheng Ren, Ndola Prata, Anu Manchikanti Gomez, Cassondra Marshall. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.06.2023.)

On an annual basis the flagellate protozoan, Giardia duodenalis, is responsible for an estimated one billion human infections of which approximately two hundred million cause disease. However, the treatment of Giardia infections is reliant on a small group of chemotherapeutic classes that have a broad spectrum of antimicrobial activity and increasing treatment failure rates. To improve this situation, we need new drugs. In this study we screened the Compounds Australia Scaffolds Library for compounds with potent and selective activity against these parasites. Unlike previous drug discovery efforts that have focused on drug repurposing, this library is comprised of commercially available synthetic compounds arranged into lead-like scaffolds to facilitate structure activity relationship assessments and de novo drug discovery. A screen of 2451 compounds in this library identified 40 hits (>50% inhibitory activity at 10 µM, over 48 h). Secondary testing identified three compounds with IC50 values <1 μM and >50-fold selectivity for parasites over mammalian cells and a hit series, CL9406, comprising compounds with potent (lowest IC50 180 nM) and selective activity for Giardia parasites. The most promising compound in this series, SN00797640, displayed selective activity against assemblage A, B, and metronidazole resistant parasites which was parasiticidal (minimum lethal concentration 625 nM) and synergistic with albendazole. SN00797640 was well-tolerated when administered to mice at doses of 50 mg/kg daily for three days paving the way for pre-clinical in vivo activity assessment.

We examined men's influence on women's interest in biomedical HIV prevention during pregnancy and breastfeeding through structured questionnaires and focus group discussions with currently or recently pregnant and breastfeeding (P/BF) women ( n = 65), men with P/BF partners ( n = 63) and mothers/mothers-in-law of P/BF women ( n = 68) in eastern and southern Africa. Data were transcribed, coded and summarised into analytical memos. Men were depicted by most participants as joint decision-makers and influencers of women's use of HIV prevention. Cultural and religious norms depicting men as heads, breadwinners and protectors of the family were cited to legitimise their involvement in decision-making. Male partner education and engagement were recommended to garner their support in women's HIV prevention. This study elucidates how P/BF women's ability to prevent HIV is shaped by traditional and contemporary gender norms in social settings and locations where the study was conducted. Findings may aid intervention design to engage men for P/BF women's effective use of microbicide and oral PrEP.

Women who acquire HIV during the pregnancy and breastfeeding periods have a higher risk of transmitting the virus to their child than women who become infected with HIV before pregnancy. We explore the context of sexual beliefs and practices that may shape both HIV risk and willingness to use HIV prevention products during pregnancy and postpartum in Malawi, South Africa, Uganda and Zimbabwe. Twenty-three single sex focus group discussions and 36 in-depth interviews took place between May and November 2018 with recently pregnant or breastfeeding women, men, mothers and mothers-in-law of pregnant or breastfeeding women, and key informants. Participants across study groups and sites (N = 232) reported various perceived benefits and harms of sex during pregnancy and postpartum. Participants discussed reasons why men might seek sex outside of the relationship. There is a critical need for alternative prevention options to protect pregnant and breastfeeding women from HIV., (© 2021. The Author(s).)