Abstract
The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The synthetic strategy applied was based on oxidative cyclization of N-(phenothiazin-3-yl)-thioamides and it was validated by the preparation of new 2-alkyl- and 2-aryl-thiazolo[5,4-b]phenothiazine derivatives. Optical properties of the series were experimentally emphasized by UV-Vis absorption/emission spectroscopy and structural features were theoretically modelled using density functional theory (DFT). In vitro activity as antileukemic agents of thiazolo[5,4-b]phenothiazine and N-(phenothiazine-3-yl)-thioamides were comparatively evaluated using cultivated HL-60 human promyelocytic and THP-1 human monocytic leukaemia cell lines. Some representatives proved selectivity against tumour cell lines, cytotoxicity, apoptosis induction, and cellular metabolism impairment capacity. 2-Naphthyl-thiazolo[5,4-b]phenothiazine was identified as the most effective of the series by displaying against THP-1 cell lines a cytotoxicity close to cytarabine antineoplastic agent.
Highlights
Heterocyclic compounds containing nitrogen and sulphur were frequently evidenced in many biological active compounds of both natural and synthetic origins
The described synthetic protocol offers a reliable route to the heterocyclic system containing benzo-fused thiazole and phenothiazine units with linear arrangement
Apart from the preparation of various 2-substituted TAPTZ derivatives, the scope of this methodology can be broadened to the preparation of novel constitutional isomers of TAPTZ when starting with different position isomers of the amino-phenothiazine precursors
Summary
Heterocyclic compounds containing nitrogen and sulphur were frequently evidenced in many biological active compounds of both natural and synthetic origins. Two heteroaromatic compounds commonly recognized for a broad spectrum of pharmacological activities are tricyclic phenothiazine (PTZ) [1] and bicyclic benzothiazole (BTA) [2], each of them with individual synthetic representatives sharing high therapeutic potency as antimicrobial, antimalarial, anthelmintic, analgesic, or anti-inflammatory drugs. The potential anticancer activity of both PTZ and BTA seemed to be of high researccahhvreionrmstaeotrpilehesost.ruebssPftirTnaeZtelytdhtueantrieivsdarbeticyvovemasm,riaecbnoldmeesdmubfoosnrtilmtyuatithoeinrgiaohlnslysthcrieeenplateitrfeiipcdhinetvroaelsttbhigeenaitzrieonnnees.urirnoglse[p4t–i6c] macatkioenth, isalso exhibited aRnteic-epnrtolyli,ftehreatpivoteeneftfiaelcta,natinctain-ccaerlmacotdivuitlyinof(CbAotMh P) TaZctiaonnd, BaTnAd isneehmibeidtiotonboef opfrhoitgehinreksienaarscehs or P-glycoinptreoretseti.nP(TPZgpde)rtirvaantisvpeso,rctofmunmcotniolyn h[7ig]h. Tohbesseercvoanbdlaebsinorpthtieonsbpaencdtra of N-(phsietunaottehdiaazt ilnoneg-3e-rywl)a-tvheileonagmthisdewsa2s ac–hearaanctderaizmedidbeyslo1wa–eer,inretesnpseictytiavnedlya, astsroenxgemdeppleifindedenicne Fofigitusre 2a by thl(eoFciogavutierorenla2oibdn).UthTVeheealbaebcstosrororpnptitciioopnnrosoppfeertc-ttbieruastyoolff-TtthhAeePsTpuZhbes3ntaityuolecsncutusbrsraettidttaucahtteedhdidginheerprivoesainttieivorngeys2., Towfhhteihleseettchhoeinazadorolaembusaontiirctption bandssuibtustaittueedntastelnoanbgleedr wa baavtehloecnhgrothmsicwsahsiftchofa4ra4–c9te8rnizme.d by lower intensity and a strong dependence of its location on the electronic properties of the substituents attached in position 2 of the thiazole unit (Figure 2b). Large Stokes shift values (Table 1) typical to phenothiazine derivatives were detected, suggesting a significant structural reorganization of the polarized excited state as compared to the ground state [30].
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