title: Rational design and synthesis of novel thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors.
abstract: A series of novel thiazolidin-4-one analogues, characterized by different substitution patterns at positions C-2 and N-3 of the thiazolidin-4-one scaffold for anti-HIV-1 activity has been investigated. Most of the compounds showed anti-HIV-1 activity at micromolar concentrations when tested in TZM-bl cells in vitro. Among the thirty-three compounds tested, compound 16 was the most potent inhibitor of HIV-1 replication against HIV-1IIIB, HIV-1ADA5, HIV-1UG070 and HIV-1VB59 (EC50=0.02, 0.08, 0.08 and 0.08 μM, respectively) with selectivity index (SI=6940, 1735, 1692 and 1692) against tested viral strains, respectively. The results of the present study suggested that the substitution of the nitro group at 6' position of the C-2 phenyl ring and 4,6-dimethylpyridin-2-yl at the N-3 position of thiazolidin-4-one had a major impact on the anti-HIV-1 activity and was found to lower cytotoxicity. The substitution of the heteroaryl ring with bromo group and bicyclic heteroaryl ring at N-3 thiazolidin-4-one was found to lower anti-HIV-1 activity and increase cytotoxicity. The undertaken docking studies thus facilitated the identification of crucial interactions between the HIV-1 RT enzyme and thiazolidin-4-one inhibitors, which can be used to design new potential inhibitors.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CDRI), Jankipuram Extension, Sector-10, Lucknow 226031, Uttar Pradesh, India.
authors.forename: Vanangamudi
authors.initials: V
authors.lastname: Murugesan
authors.affiliation: Department of Molecular Virology, National AIDS Research Institute (NARI), Pune 411026, Maharashtra, India.
authors.forename: Nandini
authors.initials: N
authors.lastname: Makwana
authors.affiliation: Department of Molecular Virology, National AIDS Research Institute (NARI), Pune 411026, Maharashtra, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Suryawanshi
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute (CDRI), Jankipuram Extension, Sector-10, Lucknow 226031, Uttar Pradesh, India.
authors.forename: Reshu
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute (CDRI), Jankipuram Extension, Sector-10, Lucknow 226031, Uttar Pradesh, India.
authors.forename: Rajkamal
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Department of Molecular Virology, National AIDS Research Institute (NARI), Pune 411026, Maharashtra, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Paranjape
authors.affiliation: Department of Molecular Virology, National AIDS Research Institute (NARI), Pune 411026, Maharashtra, India.
authors.forename: Smita
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute (CDRI), Jankipuram Extension, Sector-10, Lucknow 226031, Uttar Pradesh, India. Electronic address: sb_katti@cdri.res.in.
authors.forename: Seturam B
authors.initials: SB
authors.lastname: Katti
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Anti-HIV-1 activity; HIV-1 reverse transcriptase; NNRTIs; Thiazolidin-4-ones