Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.

Department of Medicinal Chemistry May Institute of Pharmacology Polish Academy of Sciences Smętna 12 31 343 Kraków Poland

Department of Microbiology and Immunology University of Otago Dunedin New Zealand

Department of Pharmaceutical Sciences University of Perugia Via Del Liceo 1 Perugia 06100 Italy

Department of Physical Chemistry University of Chemistry and Technology Technicka 5 16628 Prague Czech Republic

Department of Technology and Biotechnology of Drugs Faculty of Pharmacy Jagiellonian University Medical College Medyczna 9 30 688 Kraków Poland

Institute for Tuberculosis Research College of Pharmacy University of Illinois at Chicago Chicago IL USA

000      

00000naa a2200000 a 4500

001      

bmc21020175

003      

CZ-PrNML

005      

20210830101807.0

007      

ta

008      

210728s2020 fr f 000 0|eng||

009      

AR

024    7_

$a 10.1016/j.ejmech.2020.112420 $2 doi

035    __

$a (PubMed)32526553

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a fr

100    1_

$a Nizi, Maria Giulia $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

245    10

$a Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors / $c MG. Nizi, J. Desantis, Y. Nakatani, S. Massari, MA. Mazzarella, G. Shetye, S. Sabatini, ML. Barreca, G. Manfroni, T. Felicetti, R. Rushton-Green, K. Hards, G. Latacz, G. Satała, AJ. Bojarski, V. Cecchetti, MH. Kolář, J. Handzlik, GM. Cook, SG. Franzblau, O. Tabarrini

520    9_

$a Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.

650    _2

$a zvířata $7 D000818

650    _2

$a antituberkulotika $x chemická syntéza $x metabolismus $x farmakologie $x toxicita $7 D000995

650    _2

$a Cercopithecus aethiops $7 D002522

650    _2

$a synergismus léků $7 D004357

650    _2

$a inhibitory enzymů $x chemická syntéza $x metabolismus $x farmakologie $x toxicita $7 D004791

650    _2

$a HEK293 buňky $7 D057809

650    _2

$a lidé $7 D006801

650    _2

$a jaterní mikrozomy $x metabolismus $7 D008862

650    _2

$a molekulární struktura $7 D015394

650    _2

$a Mycobacterium smegmatis $x účinky léků $7 D020102

650    _2

$a Mycobacterium tuberculosis $x účinky léků $7 D009169

650    _2

$a NADH-dehydrogenasa $x antagonisté a inhibitory $7 D009245

650    _2

$a organoselenové sloučeniny $x chemická syntéza $x metabolismus $x farmakologie $x toxicita $7 D016566

650    _2

$a parazitické testy citlivosti $7 D021261

650    _2

$a fenothiaziny $x chemická syntéza $x metabolismus $x farmakologie $x toxicita $7 D010640

650    _2

$a vazba proteinů $7 D011485

650    _2

$a receptory dopaminu D2 $x metabolismus $7 D017448

650    _2

$a receptory serotoninové $x metabolismus $7 D011985

650    _2

$a vztahy mezi strukturou a aktivitou $7 D013329

650    _2

$a Vero buňky $7 D014709

655    _2

$a časopisecké články $7 D016428

700    1_

$a Desantis, Jenny $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Nakatani, Yoshio $u Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand

700    1_

$a Massari, Serena $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Mazzarella, Maria Angela $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Shetye, Gauri $u Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

700    1_

$a Sabatini, Stefano $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Barreca, Maria Letizia $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Manfroni, Giuseppe $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Felicetti, Tommaso $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Rushton-Green, Rowena $u Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand

700    1_

$a Hards, Kiel $u Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand

700    1_

$a Latacz, Gniewomir $u Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland

700    1_

$a Satała, Grzegorz $u Department of Medicinal Chemistry May Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland

700    1_

$a Bojarski, Andrzej J $u Department of Medicinal Chemistry May Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland

700    1_

$a Cecchetti, Violetta $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy

700    1_

$a Kolář, Michal H $u Department of Physical Chemistry, University of Chemistry and Technology, Technicka 5, 16628, Prague, Czech Republic

700    1_

$a Handzlik, Jadwiga $u Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland

700    1_

$a Cook, Gregory M $u Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand

700    1_

$a Franzblau, Scott G $u Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

700    1_

$a Tabarrini, Oriana $u Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy. Electronic address: oriana.tabarrini@unipg.it

773    0_

$w MED00001628 $t European journal of medicinal chemistry $x 1768-3254 $g Roč. 201, č. - (2020), s. 112420

856    41

$u https://pubmed.ncbi.nlm.nih.gov/32526553 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y p $z 0

990    __

$a 20210728 $b ABA008

991    __

$a 20210830101807 $b ABA008

999    __

$a ok $b bmc $g 1690878 $s 1140621

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2020 $b 201 $c - $d 112420 $e 20200605 $i 1768-3254 $m European journal of medicinal chemistry $n Eur J Med Chem $x MED00001628

LZP    __

$a Pubmed-20210728