Spiro heterocycles bearing piperidine moiety as potential scaffold for antileishmanial activity: synthesis, biological evaluation, and in silico studies

被引:12
作者
Mohamed, Mounir A. A. [1 ]
Kadry, Asmaa M. [1 ]
Bekhit, Salma A. [2 ]
Abourehab, Mohammed A. S. [3 ]
Amagase, Kikuko [4 ]
Ibrahim, Tamer M. [5 ]
El-Saghier, Ahmed M. M. [1 ]
Bekhit, Adnan A. [6 ,7 ,8 ]
机构
[1] Sohag Univ, Fac Sci, Chem Dept, Sohag, Egypt
[2] Alexandria Univ, High Inst Publ Hlth, Alexandria, Egypt
[3] Umm Al Qura Univ, Coll Pharm, Dept Pharmaceut, Mecca, Saudi Arabia
[4] Ritsumeikan Univ, Coll Pharmaceut Sci, Lab Pharmacol & Pharmacotherapeut, Kusatsu, Japan
[5] Kafrelsheikh Univ, Fac Pharm, Dept Pharmaceut Chem, Kafr Al Sheikh, Egypt
[6] Alexandria Univ, Fac Pharm, Dept Pharmaceut Chem, Alexandria, Egypt
[7] Alexandria Univ, Fac Pharm, Canc Nanotechnol Res Lab CNRL, Alexandria, Egypt
[8] Univ Bahrain, Coll Hlth & Sport Sci, Allied Hlth Dept, Sakhir, Bahrain
关键词
Spiro; piperidine; modelling; leishmania; ionic liquid; PTERIDINE REDUCTASE; ENANTIOSELECTIVE SYNTHESIS; MOLECULAR-DYNAMICS; DERIVATIVES; DOCKING; AGENTS; OPTIMIZATION; VITRO;
D O I
10.1080/14756366.2022.2150763
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 mu M and 0.50 mu M, respectively, compared to 8.08 mu M of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1.
引用
收藏
页码:330 / 342
页数:13
相关论文
共 54 条
  • [1] Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
    Abraham, Mark James
    Murtola, Teemu
    Schulz, Roland
    Páll, Szilárd
    Smith, Jeremy C.
    Hess, Berk
    Lindah, Erik
    [J]. SoftwareX, 2015, 1-2 : 19 - 25
  • [2] In vitro anti-Leishmania activity and molecular docking of spiro-acridine compounds as potential multitarget agents against Leishmania infantum
    Almeida, Fernanda S.
    Sousa, Gleyton L. S.
    Rocha, Juliana C.
    Ribeiro, Frederico F.
    de Oliveira, Marcia Rosa
    de Lima Grisi, Teresa Cristina Soares
    Araujo, Demetrius A. M.
    Nobre, Michelangela S. de C.
    Castro, Rosane N.
    Amaral, Ian P. G.
    Keesen, Tatjana S. L.
    de Moura, Ricardo Olimpio
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2021, 49
  • [3] Enantioselective synthesis of piperidine, indolizidine, and quinolizidine alkaloids from a phenylglycinol-derived δ-lactam
    Amat, M
    Llor, N
    Hidalgo, J
    Escolano, C
    Bosch, J
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (05) : 1919 - 1928
  • [4] Mechanistic insight on the remdesivir binding to RNA-Dependent RNA polymerase (RdRp) of SARS-cov-2
    Arba, Muhammad
    Wahyudi, Setyanto Tri
    Brunt, Dylan J.
    Paradis, Nicholas
    Wu, Chun
    [J]. COMPUTERS IN BIOLOGY AND MEDICINE, 2021, 129 (129)
  • [5] The use of the aza-Diels-Alder reaction in the synthesis of pinidine and other piperidine alkaloids
    Bailey, PD
    Smith, PD
    Morgan, KM
    Rosair, GM
    [J]. TETRAHEDRON LETTERS, 2002, 43 (06) : 1071 - 1074
  • [6] POTENTIAL ANTICANCER AGENTS .26. SPIN LABELED NITROSOUREAS
    BARACU, I
    DOBRE, V
    NICULESCUDUVAZ, I
    [J]. JOURNAL FUR PRAKTISCHE CHEMIE, 1985, 327 (04): : 667 - 674
  • [7] Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs against Leishmaniasis and Trypanosomiases
    Battista, Theo
    Colotti, Gianni
    Ilari, Andrea
    Fiorillo, Annarita
    [J]. MOLECULES, 2020, 25 (08):
  • [8] New pyrazolylpyrazoline derivatives as dual acting antimalarial-antileishamanial agents: synthesis, biological evaluation and molecular modelling simulations
    Bekhit, Adnan A.
    Lodebo, Eskedar T.
    Hymete, Ariaya
    Ragab, Hanan M.
    Bekhit, Salma A.
    Amagase, Kikuko
    Batubara, Afnan
    Abourehab, Mohammed A. S.
    Bekhit, Alaa El-Din A.
    Ibrahim, Tamer M.
    [J]. JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2022, 37 (01) : 2320 - 2333
  • [9] Investigation of the anti-inflammatory and analgesic activities of promising pyrazole derivative
    Bekhit, Adnan A.
    Nasralla, Sherry N.
    El-Agroudy, Eman J.
    Hamouda, Nahla
    Abd El-Fattah, Ahmed
    Bekhit, Salma A.
    Amagase, Kikuko
    Ibrahim, Tamer M.
    [J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2022, 168
  • [10] Leishmania treatment and prevention: Natural and synthesized drugs
    Bekhit, Adnan A.
    El-Agroudy, Eman
    Helmy, Aliaa
    Ibrahim, Tamer M.
    Shavandi, Amin
    Bekhit, Alaa El-Din A.
    [J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 160 : 229 - 244