title: Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents.
abstract: In an attempt to explore novel and more potent antileishmanial compounds to diversify the current inhibitors, we pursued a medicinal chemistry-driven strategy to synthesize novel scaffolds with common pharmacophoric features of dihydropyrimidine and chalcone as current investigational antileishmanial compounds. Based on the reported X-ray structure of Pteridine reductase 1 (PTR1) from Leishmania major, we have designed a number of dihydropyrimidine-based derivatives to make specific interactions in PTR1 active site. Our lead compound 8i has shown potent in vitro antileishmanial activity against promastigotes of L. Major and Leishmania donovani with IC50 value of 0.47 μg/ml and 1.5 μg/ml respectively. The excellent in vitro activity conclusively revealed that our lead compound is efficient enough to eradicate both visceral and topical leishmaniasis. In addition, docking analysis and in silico ADMET predictions were also carried out. Predicted molecular properties supported our experimental analysis that these compounds have potential to eradicate both visceral and topical leishmaniasis.
authors.affiliation: Department of Chemistry, Hazara University, Mansehra 21120, Pakistan; Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan. Electronic address: umerrashid@ciit.net.pk.
authors.forename: Umer
authors.initials: U
authors.lastname: Rashid
authors.affiliation: Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
authors.forename: Riffat
authors.initials: R
authors.lastname: Sultana
authors.affiliation: Department of Animal Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Nargis
authors.initials: N
authors.lastname: Shaheen
authors.affiliation: Department of Pharmacy, University of Lahore, Defence Road Campus, Lahore 53700, Pakistan.
authors.forename: Syed Fahad
authors.initials: SF
authors.lastname: Hassan
authors.affiliation: Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
authors.forename: Farhana
authors.initials: F
authors.lastname: Yaqoob
authors.affiliation: Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
authors.forename: Muhammad Jawad
authors.initials: MJ
authors.lastname: Ahmad
authors.affiliation: Department of Chemistry, Hazara University, Mansehra 21120, Pakistan.
authors.forename: Fatima
authors.initials: F
authors.lastname: Iftikhar
authors.affiliation: Department of Biochemistry, Hazara University, Mansehra 21120, Pakistan.
authors.forename: Nighat
authors.initials: N
authors.lastname: Sultana
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Saba
authors.initials: S
authors.lastname: Asghar
authors.affiliation: Department of Biochemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan; Rector Office, International Islamic University, Islamabad 44000, Pakistan.
authors.forename: Masoom
authors.initials: M
authors.lastname: Yasinzai
authors.affiliation: Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan; Pakistan Council for Science and Technology, G-5/2, Islamabad, Pakistan.
authors.forename: Farzana Latif
authors.initials: FL
authors.lastname: Ansari
authors.affiliation: Department of Animal Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. Electronic address: nqureshi@qau.edu.pk.
authors.forename: Naveeda Akhter
authors.initials: NA
authors.lastname: Qureshi
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D007893:Leishmania donovani / Q000187:drug effects*; D018320:Leishmania major / Q000187:drug effects*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D011743:Pyrimidines
keywords: Chalcones; Dihydropyrimidine; Docking; Leishmaniasis; Rigidification; Structure based drug design