title: N-Alkyl/aryl-4-(3-substituted-3-phenylpropyl)piperazine-1-carbothioamide as dual-action vaginal microbicides with reverse transcriptase inhibition.
abstract: The growing population and health-care burden (due to STIs and HIV) imposes a particular economic crisis over resource-poor countries. Thus a novel approach as vaginal microbicides emerges as integrated tool to control both population and anti-STIs/HIV. Our continued efforts in this field led to the synthesis of fifteen N-alkyl/aryl-4-(3-substituted-3-phenylpropyl) piperazine-1-carbothioamide (12-26) derivatives as topical vaginal microbicides which were evaluated for anti-Trichomonas, spermicidal, antifungal and reverse transcriptase (RT) inhibitory activities. All compounds were also tested for preliminary safety through cytotoxicity assays against human cervical cell line (HeLa) and the vaginal flora, Lactobacillus. Docking studies were performed to gain an insight into the binding mode and interactions of the most promising compound 12 [oxo derivative], comprising of reverse transcriptase (RT) inhibitory (72.30%), spermicidal (MEC 0.01%), anti-Trichomonas (MIC 46.72 μM) and antifungal (MIC 9.34-74.8 μM) activities, along with its hydroxyl (17) and O-alkylated 4-trifluoromethylphenoxy (22) derivative, with similar activities. The stability of compound 12 in simulated vaginal fluid (SVF) and its preliminary in vivo pharmacokinetics performed in female NZ-rabbits signifies its clinical safety in comparison to marketed spermicide Nonoxynol-9.
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Veenu
authors.initials: V
authors.lastname: Bala
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Dhanaraju
authors.initials: D
authors.lastname: Mandalapu
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Sonal
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Santosh
authors.initials: S
authors.lastname: Jangir
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Kushwaha
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Chhonker
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Hardik
authors.initials: H
authors.lastname: Chandasana
authors.affiliation: Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Shagun
authors.initials: S
authors.lastname: Krishna
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Kavita
authors.initials: K
authors.lastname: Rawat
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Atul
authors.initials: A
authors.lastname: Krishna
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Mala
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Urology, King George Medical University, Lucknow 226003, India.
authors.forename: Satya N
authors.initials: SN
authors.lastname: Sankhwar
authors.affiliation: Microbiology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Shukla
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Department of Urology, King George Medical University, Lucknow 226003, India.
authors.forename: Rabi S
authors.initials: RS
authors.lastname: Bhatta
authors.affiliation: Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Rajkamal
authors.initials: R
authors.lastname: Tripathi
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
authors.affiliation: Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: vlscdri1@rediffmail.com.
authors.forename: Vishnu L
authors.initials: VL
authors.lastname: Sharma
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007779:Lactobacillus acidophilus / Q000187:drug effects; D008297:Male; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013089:Spermatocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013094:Spermatozoa / Q000187:drug effects; D013329:Structure-Activity Relationship; D013854:Thioamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014246:Trichomonas vaginalis / Q000187:drug effects; D014621:Vagina / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D013089:Spermatocidal Agents; D013854:Thioamides; D012194:RNA-Directed DNA Polymerase
keywords: Microbicide; NNRTI; Nonoxynol-9; Spermicide; Thiourea