title: Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents.
abstract: BACKGROUND
  Tributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes.
  
  
  METHODS
  ADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity.
  
  
  RESULTS
  Results indicate partial compliance of compounds with drug-likeliness rules. Ch-409 complies with WDI and Lipinski rules. ADMET profile prediction shows strong plasma protein binding except for Ch-409, low to high GI absorption and BBB penetration (Cbrain/Cblood= 0.942-11; caco-2 cells permeability 20.13-26.75 nm/sec), potential efflux by P-glycoprotein, metabolism by CYP3A4, medium inhibition of hERG, mutagenicity and capacity to be detoxified by glutathionation and glucuronidation. Molecular targets include proteases, enzymes, membrane receptors, transporters and ion channels where Ch-409 targets membrane receptors only. Compounds are significantly (p < 0.05) cytotoxic against HepG2 cell line and leishmania as compared with normal isolated lymphocytes. Ch-459 indicates highest toxicity against leishmania (mortality 97.9 ± 3.99%; LC50 0.323 ± 0.002 μg/mL) whereas Ch-409 possesses maximum cytotoxicity against HepG2 cell line (IC50 0.08 ± 0.001 μg/mL) as well as 97.5 ± 1.98% (LC50 0.954 ± 0.158 μg/mL) mortality of leishmania promastigotes. It was observed that antileishmanial effect was reduced by 16.38%-34.38% and 15-38.2% in the presence of NaN3and mannitol respectively. PK inhibition and reactive oxygen species production are possible mechanisms for cytotoxicity.
  
  
  CONCLUSIONS
  Selected carboxylate derivatives of tributyltin (IV) complexes possess significant antileishmanial and cytotoxic potential. These are promising compounds for the development of antileishmanial and anticancer drugs. Graphical Abstract Carboxylate derivatives of tributyltin (IV) complexes as anticancer and antileishmanial agents.
authors.affiliation: Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
authors.forename: Durdana
authors.initials: D
authors.lastname: Waseem
authors.affiliation: Department of Chemistry, Allama Iqbal Open University, H-8, Islamabad, 44000, Pakistan.
authors.forename: Arshad Farooq
authors.initials: AF
authors.lastname: Butt
authors.affiliation: Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
authors.forename: Ihsan-Ul
authors.initials: IU
authors.lastname: Haq
authors.affiliation: Department of Chemistry, Allama Iqbal Open University, H-8, Islamabad, 44000, Pakistan.
authors.forename: Moazzam Hussain
authors.initials: MH
authors.lastname: Bhatti
authors.affiliation: Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan. gmkhan@qau.edu.pk.
authors.forename: Gul Majid
authors.initials: GM
authors.lastname: Khan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D018938:Caco-2 Cells; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014220:Trialkyltin Compounds / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D047428:Protein Kinase Inhibitors; D014220:Trialkyltin Compounds
keywords: ADMET; Anticancer; Antileishmanial; Organotin (IV); Protein kinase inhibition