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In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule\u2013based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Further, the highly lipoidal blood\u2013brain barrier (BBB) limits the uptake of many therapeutic molecules into the brain and is a complicating factor in the development of new agents to treat neurodegeneration. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule\u2013based novel approaches to target NDDs over the last few decades, such as designing lipophilic molecules and applying prodrug strategies. Attempts have been made to utilize a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web\u2013based computational tools. To increase the clinical success of these drug candidates, an <jats:italic>in\u2005vitro<\/jats:italic> assay modeling the BBB has been utilized by medicinal chemists in the pre\u2013clinical phase as a further screening measure of small organic molecules. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs, with the intention of increasing our awareness of neurodegenerative therapeutics.<\/jats:p>","DOI":"10.1002\/cmdc.202300705","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T12:33:51Z","timestamp":1707395631000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Current Small Molecule\u2013Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5716-3992","authenticated-orcid":false,"given":"Nitesh","family":"Sanghai","sequence":"first","affiliation":[{"name":"College of Pharmacy Rady Faculty of Health Science University of Manitoba  Winnipeg MB R3E 0T5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1026-5661","authenticated-orcid":false,"given":"Billy","family":"Vuong","sequence":"additional","affiliation":[{"name":"College of Pharmacy Rady Faculty of Health Science University of Manitoba  Winnipeg MB R3E 0T5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3905-7509","authenticated-orcid":false,"given":"Ahmet","family":"Burak Berk","sequence":"additional","affiliation":[{"name":"College of Pharmacy Rady Faculty of Health Science University of Manitoba  Winnipeg MB R3E 0T5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Shaharyar K.","family":"Afridi","sequence":"additional","affiliation":[{"name":"College of Pharmacy Rady Faculty of Health Science University of Manitoba  Winnipeg MB R3E 0T5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9774-8685","authenticated-orcid":false,"given":"Geoffrey K.","family":"Tranmer","sequence":"additional","affiliation":[{"name":"College of Pharmacy Rady Faculty of Health Science University of Manitoba  Winnipeg MB R3E 0T5 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"e_1_2_14_1_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2021.776847"},{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-2667(20)30190-0"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0244-7"},{"issue":"18","key":"e_1_2_14_4_1","first-page":"2318","volume":"12","author":"Sanghai N.","year":"2023","journal-title":"An Integrated View. 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