Abstract
Twenty-three thiazolin-4-ones were synthesized starting from phenylthioamide or thiourea derivatives by condensation with α-monochloroacetic acid or ethyl α-bromoacetate, followed by substitution in position 5 with various arylidene moieties. All the synthesized compounds were physico-chemically characterized and the IR (infrared spectra), 1H NMR (proton nuclear magnetic resonance), 13C NMR (carbon nuclear magnetic resonance) and MS (mass spectrometry) data were consistent with the assigned structures. The synthesized thiazolin-4-one derivatives were tested for antifungal properties against several strains of Candida and all compounds exhibited efficient anti-Candida activity, two of them (9b and 10) being over 500-fold more active than fluconazole. Furthermore, the compounds’ lipophilicity was assessed and the compounds were subjected to in silico screening for prediction of their ADME-Tox properties (absorbtion, distribution, metabolism, excretion and toxicity). Molecular docking studies were performed to investigate the mode of action towards the fungal lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme. The results of the in vitro antifungal activity screening, docking study and ADME-Tox prediction revealed that the synthesized compounds are potential anti-Candida agents that might act by inhibiting the fungal lanosterol 14α-demethylase and can be further optimized and developed as lead compounds.
Highlights
Based on the proven biological potential of the compounds with thiazolin-4-one core in their structure and as a continuation to our increased interest in the chemistry of thiazole and its derivatives [17], we report the synthesis of new thiazolin-4-ones diversely substituted in positions 2 and 5, with structures that include, in addition to the thiazolin-4-one ring, other heterocycles with known biological potential such as thiazole [18] and chromone [19]
Plates were incubated under normal atmospheric conditions 25 ◦carbon atoms (Cs) for 48 h (Candida albicans ATCC 10231, Candida albicans ATCC 18804, Candida krusei ATCC 6258, Candida parapsilosis ATCC 22019), and minimum inhibitory concentration (MIC) values have been determined by recording the optical density at 600 nm using a spectroscopically method with a microplate reader Biotek Synergy HT
The newly synthesized compounds were characterized by quantitative elemental analysis, IR, 1H NMR, 13C NMR and MS
Summary
Of the five-membered heterocyclic rings containing sulfur and nitrogen, the thiazolin-4-ones are considered biologically privileged molecules and enjoy special attention from researchers in the field of medicinal chemistry due to their multifarious biological activities and good tolerability in humans [1,2]. The lanosterol 14α-demethylase (or CYP51A1) is a key enzyme in the synthesis of ergosterol, an essential component of the fungal cell membrane and constitutes an important biological target for the most popular class of antifungals (the azoles) [13]. From the physicochemical properties of biologically active compounds, lipophilicity is of great importance and should be determined from the early stages of drug development because it affects basic steps of a drug’s pharmacokinetics and pharmacodynamics, such as absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) [14]. SSuubbsseeqquueennttllyy, ,thtehepopsiotisoitnio5nof5thoefsuthbestitsuutbesdti2tu-atemdin2o--athmiainzool-itnh-i4a-zoonliens-w4-aosnmesodwualsatemdotdhurolautgehd KthnrooeuvgehnaKgneolecvoenndagenelsactoinodneonfsatthioenoobftathineeodbtianitneerdmiendtieartmesed2i,at5esan2,d58a,nwd i8t,hwviathriovuarsioaursomaraotmicaotirc hoerthereotearrooamroamticatailcdaelhdyedheysd,eisn, ianbasoblsuotleuteethetahnaonloalnadndininthtehepprerseesnenceceooffaannhhyyddrroouussssooddiiuumm aacceettaattee,, iinn oorrddeerrtotooobbtatainin, ,iningogoododyiyeiledlds s(5(95%9%–9–49%4%) )thtehe2-2(a-(lalyllly/la/aryryl-la-ammininoo)-)5-5-a-arryylildideennee--tthhiiaazzoolliinn--44--oonneess 33aa––hh,, 66aa––ee aanndd 99aa––ee ((SScchheemmee 22)). MMaassss ssppeeccttrraa wweerree rreeccoorrddeedd ffoorr bbootthh tthhee 55--uunnssuubbssttiittuutteedd tthhiiaazzoolliinn--44--oonnee ddeerriivvaattiivveess 22,, 55,, 88,, 1100,, aanndd 1111 aanndd tthhee 55--aarryylliiddeennee--tthhiiaazzoolliinn--44--oonneess 33aa––hh,, 66aa––ee aanndd 99aa––ee,, wwhhiicchh ggaavvee iinnffoorrmmaattiioonn rreeggaarrddiinngg tthhee ffrraaggmmeennttaattiioonn ooff tthhee ccoommppoouunnddss wwiitthh tthheeiirr ccoorrrreessppoonnddiinngg mmaassss aanndd,, iinn aallll ccaasseess,, rreevveeaalleedd tthhee ccoorrrreeccttmmoolleeccuullaarriioonnppeeaakkss((MM++ oorr MM ++11)),,aassssuuggggeesstteeddbbyytthheeiirrmmoolleeccuullaarrffoorrmmuullaass. TthheeirpihmemnoeldiciaOteHvigcrionuitpy.pTrhoetopnhaepnpoeliacrOedHagsraousipngplreottaotn9a.3p1p–e9a.r3e5dpapsma. sTinhgelpetroatto9n.s31o–f9t.h3e5mppetmho. xTyhgerporuoptornesoonfattheed maseathsoinxgylegtroinutphere3s.o8n3aptepdmarseagisoinngolfetthienstpheec3tr.u83mp. pTmhe r1e3CgioNnMoRf tshpeescptreactoruf mth.eTshyent1h3CesiNzeMdRcospmepctoruanodfsthweesryenctohnesiszteedntcowmitphotuhnedpsrwopeoresecdonsstrisutcetnutrwesi.th the proposed structures
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