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Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani.

ABSTRACT: A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH₂O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC₅₀ value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

SUBMITTER: Hassan AHE

PROVIDER: S-EPMC8386730 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani.

Hassan Ahmed H E AHE Phan Trong-Nhat TN Yoon Seolmin S Lee Cheol Jung CJ Jeon Hye Rim HR Kim Seung-Hwan SH No Joo Hwan JH Lee Yong Sup YS

Journal of enzyme inhibition and medicinal chemistry 20211201 1

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the m ...[more]

PMID: 34425714

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Project description:Neglected tropical diseases (NTDs) pose a significant public health challenge in tropical and subtropical regions, particularly in the Kingdom of Saudi Arabia (KSA), where epidemiological data remain scarce. These diseases disproportionately affect vulnerable populations, leading to chronic morbidity and economic burdens. Understanding their distribution and burden is crucial for effective public health interventions. This study aimed to systematically evaluate the prevalence, distribution, and etiological patterns of NTDs in KSA, identifying key research gaps and informing future policy directions. A systematic review and meta-analysis were conducted on peer-reviewed studies published between 1950 and 2024 that investigated NTDs in humans in KSA. Ninety-four articles met the inclusion criteria. The majority (69.15%, n = 65) were published after 2010, with most studies concentrated in the western (n = 35, 37.23%) and southwestern (n = 15, 15.96%) regions, areas known for environmental and socioeconomic factors that may contribute to disease transmission. Protozoal NTDs were the most frequently reported (n = 28, 29.78%), followed by viral (n = 26, 27.66%), helminthic (n = 18, 19.15%), and ectoparasitic (n = 9, 9.57%) infections. Bacterial (n = 5, 5.32%), fungal (n = 4, 4.26%), and venom-related (n = 4, 4.26%) NTDs were less commonly reported. Meta-analysis yielded pooled prevalence estimates of leishmaniasis at 0.59 (95% CI: 0.38-0.77, I² = 94.2%) and dengue at 0.20 (95% CI: 0.05-0.53, I² = 98.8%), highlighting a substantial disease burden and high heterogeneity among studies. The findings emphasize the urgent need for strengthened national surveillance, improved diagnostic capacity, and region-specific interventions to control NTDs in KSA. Future research should focus on underrepresented regions, expand community-based epidemiological studies, and integrate cross-border surveillance strategies to mitigate disease importation risks. By addressing these gaps, KSA can enhance its preparedness and contribute to global NTD elimination efforts.

Project description:Lymphatic filariasis (LF) and soil-transmitted helminths (STH) have been targeted since 2000 in Haiti, with a strong mass drug administration (MDA) program led by the Ministry of Public Health and Population and its collaborating international partners. By 2012, Haiti's neglected tropical disease (NTD) program had reached full national scale, and with such consistently good epidemiological coverage that it is now able to stop treatment for LF throughout almost all of the country. Essential to this success have been in the detail of how MDAs were implemented. These key programmatic elements included ensuring strong community awareness through an evidence-based, multi-channel communication and education campaign facilitated by voluntary drug distributors; strengthening community trust of the drug distributors by ensuring that respected community members were recruited and received appropriate training, supervision, identification, and motivation; enforcing a "directly observed treatment" strategy; providing easy access to treatment though numerous distribution posts and a strong drug supply chain; and ensuring quality data collection that was used to guide and inform MDA strategies. The evidence that these strategies were effective lies in both the high treatment coverage obtained- 100% geographical coverage reached in 2012, with almost all districts consistently achieving well above the epidemiological coverage targets of 65% for LF and 75% for STH-and the significant reduction in burden of infection- 45 communes having reached the target threshold for stopping treatment for LF. By taking advantage of sustained international financial and technical support, especially during the past eight years, Haiti's very successful MDA campaign resulted in steady progress toward LF elimination and development of a strong foundation for ongoing STH control. These efforts, as described, have not only helped establish the global portfolio of "best practices" for NTD control but also are poised to help solve two of the most important future NTD challenges-how to maintain control of STH infections after the community-based LF "treatment platform" ceases and how to ensure appropriate morbidity management for patients currently suffering from lymphatic filarial disease.

Project description:BackgroundCommunity drug distributors or neglected tropical disease (NTD) volunteers have played a crucial role in ensuring the success of mass drug administration (MDA) programs using preventive chemotherapy (PC) for lymphatic filariasis, onchocerciasis, schistosomiasis, trachoma and soil transmitted helminths. In recent years however, a noticeable decline in motivation of some of these volunteers has been perceived, potentially negatively impacting the success of these programs. Potential hypotheses for this change in motivation include the long duration of many MDA programs, the change in sociocultural environments as well as the changes to the programs over time. This literature review identifies factors that affect NTD volunteer performance and motivation, which may be used to influence and improve future programming.Methodology/principal findingsA systematic search was conducted to identify studies published between January 1995 and September 2016 that investigate factors pertaining to volunteer motivation and performance in NTD drug distribution programs. Searches from several databases and grey literature yielded 400 records, of which 28 articles from 10 countries met the inclusion criteria. Quality assessment of studies was performed using the Critical Appraisal Skills Programme(CASP) checklist. Data pertaining to motivation, performance, retention and satisfaction was extracted and examined for themes. Recurring themes in the literature included monetary and material incentives, intrinsic motivation, gender, cost to participate, and health systems and community support. Of these, community support and the health system were found to be particularly impactful. Very few studies were found to explicitly look at novel incentives for volunteers and very few studies have considered the out of pocket and opportunity costs that NTD volunteers bear carrying out their tasks.Conclusions/significanceThere is currently great interest in incorporating more attractive incentive schemes for NTD volunteers. However, our results show that the important challenges that volunteers face (cultural, health systems, financial and community related) may have less to do with financial incentives and may actually have a larger impact on their motivation than has previously been understood. Further integration of NTD programs into existing health systems is expected to improve the NTD volunteer working environment. Relevant community engagement related to the MDA program should also provide the supportive environment needed in the community to support NTD volunteers. Programs need to consider these issues to improve working conditions for NTD volunteers.

Dataset Information

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of Leishmania donovani.

Publications

Pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs as possible candidates against neglected tropical diseases (NTDs): identification of hit compounds towards development of potential treatment of <i>Leishmania donovani</i>.

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