Huisman, Henderikus Obias

English

The second chapter of this thesis contains a survey of the most important antibiotics, which have been isolated up to the present. It will be seen that several of them are derivatives of quinones; a disadvantage is often their toxicity. We therefore tried to prepare other quinones in the hope of obtaining active compounds of lower toxicity. In this thesis are described a number of derivatives of p-benzo-quinone and p-toluquinone, which possess other groupings than the natural antibiotics of the quinone type viz. fumigatin (3-hydroxy-4-methoxy-2,5-toluquinone) and spinulosin (3, 6-dihydroxy-4-methoxy-2, 5-toluquinone) and which differ from the quinones prepared and tested by Oxford and his collaborators. ... Zie: Summar

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   University of GroningenChinonen en chinonderivaten en hun invloed op micro-organismenHuisman, Henderikus ObiasIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1948Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Huisman, H. O. (1948). Chinonen en chinonderivaten en hun invloed op micro-organismen. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 07-06-202282SUMMARY.The second chapter of this thesis contains a survey of the mostimportant antibiotics, which have been isolated up to the present:It will be seen that several of them are derivatives of quinones;a disadvantage is often their toxicity.'We therefore tried to prepare other quinones in the hope ofobtaining active compounds of lower toxicity.In the thesis are described a number of derivatives of p-benzo-quinone and p-toluquinone, which possess other groupings than thenatural antibiotics of the quinone type viz. fumigatin (3-hydroxy-4-methoxy-2,5-toluquinone) and spinulosin (3,6-dihydroxy-4-me-thoxy-2,5-toluquinone) and which differ from the quinones preparedand tested by Oxford and his collaborators.The preparation of a number of hydroquinones and of hydro-quinone esters is also described. The compounds prepared arelisted in the left of Table I *).The unknown 3-chloro-2,5,6-trimethoxybenzoquinone-1,4 wasprepared as follows:o o ol\ lr. rl,/,, ncr ,/\o."3 ct/\o.*r,l l  l l  - +  l l  l l  - >  l l  l lHaco\//ocHa HsCo\/oCHs H3co\//ocHg888Diaminoquinones of this formula have been synthesized by thereaction of trichlorotoluquinone-2,5 with amines.3" , . . í  ] INHRRHN\/2crI2-Methoxy-3,6-bis-oxyethylaminobenzoquinone-1,4 has resultedfrom the reaction between 2,6-dimethoxybenzoquinone-1,4 andaminoethanol. PcH2oH.cH'  t * ' / \r l l lH3Co \ lNH.  CHz .  CH2OHt l*) The Tables will be Íound atothe end of this thesis.ns a survey of the rnostrlated up to the present:Jerivatives of quinones;uinones in the hope oficity.derivatives of p-benzo-lther groupings than the;. fumigatin (3-hydroxy-n (3,6-dihydroxy-4-me-m the quinones prepared)rs.quinones and of hydro-rmpounds prepared are.ybenzoquinone-1,4 wasol l,,/\. t í  ÈocH3u.co\7ocH3l loreen synthesized by theamines.luinone-I,4 has resulted<ybenzoquinone-1,4 andÍ 2 .  cHzoHs thesis.83By reducing the quinones with SnCl, and diluted hydrochloricacid the corresponding hydroquinones were prepared.The di-esters (diacetates and dibutyrates) of the hydroquinoneshave been obtained by reducing the quinones with zinc in a mixtureof the organic acid and its anhydride (,,reductive acylation").Diphosphates and bis-p-aminobenzoates were prepared fromhydroquinones and phosphorus oxychloride, or p-aminobenzoyl-chloride hydrochloride respectively.2,6-Dimethoxyhydroquinone octa-acetyl-bis-B-glucoside has beensynthesized from the hydroquinone and B-penta-acetyl glucose intoluene using p-toluene sulphonic acid as a catalyst.However, on saponifying the octa-acetate in alcaline alcohol thecompound decomposed.The biological activity of all these compounds, so far as theyare soluble in water, has been tested in aitro against a yeast, variousmoulds and Gram-positive and Gram-negative micro-organisms.The toxicity has been determined in white mice, by oral admi-nistration of the quinones, hydroquinones and di-esters and byintraperitoneal injection of the di-esters. The chemotherapeuticactivity has been investigated in rvhite mice injected with a lethaldose of pneumococci.In Table I, figures are given for the inhibiting effects of thesecompounds on the growth of the yeast Sacchqro?nyces cereaisiae andof the moulds Aspergillus niger, Mucor rnce?nosLts, Penicilliummeleagrinum and Penicillium notatum.The figures indicate the lowest concentration of the compoundsfor which a visible growth-inhibiting effect could be observed, incomparison with the control tubes.It must be noted, that in these series no investigations were madewith concentrations ) I : 50.000. It is possible therefore, thatinhibition of growth may occur at higher concentrations.The dilutions of the compounds with the broth cultures weremade in the usual manner.The compounds marked with * are too sparingly soluble to giveconcentrations I : 50.000; investigations were therefore made withsaturated solutions.The yeast and the moulds were cultured on the well-knownbroth cultures.84The figures in Table II indicate the lorvest concentrations of thecompounds for rvhich a visible grorvth-inhibiting effect, in com-parison with the control tubes, could be observed with the Gram-positive bacteria Streptococcus haernolyticws and Diplococcus pnew-moniae (type I) and with the Gram-negative Bacillus proteus.No investigations were made with concentrations ) I : 50.000.Investigations on the growth-inhibiting effects of the compoundson the Gram-positive Síaphylococcrts &Ltreus and the Gram-negativeBacillus col'i diff.er from those described before.In these series experiments were made r,vith concentrations) I : 50.000, as far as possible on account of the very low solu-bility in water of most compounds of the quinone type.Furthermore, culture tubes were sown with an initial inoculumvarying from 1600-13.000 viable org;anisms; the exact number ofthem in each series was determined afterwards in the usual manner.In this way the possible influence of different inoculae on thegrowth was eliminated.The figures in Table III indicate the limiting concentrations ofthe compounds tested.The Table on page 64 shows clearly how the dilutions havebeen made.Compounds numbered l-3 have already been tested by Oxfordon Staphylococcus &xlleus.Table IV shows the results of an investigation on the toxicity ofthe quinones, hydroquinones and water- or fat-soluble di-esters, byoral administration to white mice in different doses. Control mice'were given orally 40 mgr ,,Dagénan" suspended in water.Inaitro strongly antibacterial quinones and hydroquinones provedto be also very toric to Ïrigher organisms. The tolerable dose of suchcompounds for a mouse of 20 gram weight varies from 2.5-5 mgr.The di-esters proved to be rather non-toxic. Doses of.2O-40 mgrare well tolerated. However, intraperitoneal injection of.20 mgr ofthese di-esters, dissolved in water or arachis oil, causes deathafter l-24 hours, as shown in Table V.Finally, Table VI shows the results of an investigation of thechemotherapeutic activity of these compounds, in white miceinjected with a lethal dose of pneumocci.The drugs, dissolved, or suspended in water or arachis oil, wereadministered bv a stomach tube.;t concentrations of theLibiting effect, in com-,s€rv€d with the Gram-and Diplococcus pnew-we Baci l lus protews.:ntrat ions ) l  :50.000.:fects of the compoundsand the Gram-negativerefore..e r.vith concentrations. of the very low solu-: quinone type.'ith an initial inoculumrs; the exact number of:ds in the usual manner.fferent inoculae on theriting concentrations of.ow the dilutions have'been tested by Oxford;ation on the toxicity offat-soluble di-esters, byent doses. Control mice>ended in lvater.d hydroquinones provedire tolerable dose of suchvaries from 2.5-5 mgr.:ic. Doses of 20-40 mgrrl injection of 20 mgr of'achis oil. causes deathan investigation of therounds, in white micerter or arachis oil, were85F'rom the results of these investigations, one could conclude that,on account of their general toxic reactions and their antibacterialinactivity in, aiao, quinones and hydroquinones rvhich are stronglyantibactertal in uitro, have presumably little or no therapeutic value.The di-esters of the hydroquinones, although rather non-toxic onoral adrninistration, appear to be also inactïve in ui",;o. This conclu-sion is in accordance with those of Glock, Thorp, flngar anrlWien, based on their biological investigations on 4,6-dimethoxy-toluquinone, which is highly active in aitro.The last chapter of this thesis contains a discussion of therelationship between chemical constitution and biological activityof a number of antibiotics, in connection with the hypothesis ofCavailito and his collaborators. As is well known, Cavallito andother investigators have shown, that several antibiotics mav beinactivated by adding thiol compounds to the culture medium.This fact lead Cavallito to the hypothesis, that these antibioticspossibly act by blocking essential SH-systems of the bacterial cell.Attention has been called to the possibility that rnany antibio-tics, as well as other antibacterial compounds, possess ,,activegroupings", which mav react with the SH-systems of the micro-organism. This point of view has lead us to the attractive assump-tion to divide those compounds in the following classes:A. Compounds possessing ,,active" -C:C-groupings, thatmay react with thiol compounds, e.g. according the followingscheme:R S Hró!óLc-+HSR*-J-é_l_o oPossibly, the antibiotics penicillic acid, patulin, mycophenolicacid, the ,,plant antibiotic" proto-anemonine, the antibacterialcompounds of the acrylophenone type, as well as some compoundspossessing unsaturated lactone structures, belong to this class.B. Compounds possessing ,,active" oxide groupings, which mayreact with thiol compounds, e.g. according thc schemes:R'-As- o + IHSR + n'--e.{sR -1- Hro\snR'-S-S-R' + 2 HSR + 2 R'-S-S-R + I{2Ol to86Possibly, the antibiotic iodinin, the ,,plant antibiotic" allicinand also those organic arsenic compounds, which in aiao afteroxidation or reduction form alkylarsen oxides RAsO, belong tothis class.C. Compounds, possessing oxido-reduction systems able tooxidise SH-groups to the corresponding -S-S-compounds, e.g.compounds with a quinone structure, some dyes and the antibioticsgliotoxin and chlororaphin.Horvever, it must be noted, that some quinones also react withSH-compounds, through addition at the double bonds of thequinone molecule.All these compounds may be considered as ,,substances thiolopri-ves", which according to Bacq (Experientia II, 349,885 (1946))cause characteristic phenomena in the organism, probably dueto their reaction rvith the thiol groups of enzyme systems. Examples:HrO, (oxidation of SH-groups), heavy metals (Hg, Cu etc. formingmetal complexes with thiols), organic halogen compounds, such ashalogen acetic acids, mustard gas, etc., in which the ,,active"halogen atom can react with SH-groups, either by substitutionor dehydrogenation.Most compounds, mentioned under A, B and C, have been provedto be toxic for higher organisms. Therefore it appears, that thesecompounds are rather non-specific in reacting with SH-systems.However, by synthesizing a large number of products with,,active" groupings, it may be possible to obtain compounds whichmight prove to be more specific in reacting with SH-systems andpossibly might be of therapeutic value.LIST OF I{EW COMPOUNDS.C.HrOnPrNa, 2-methyl-5-methoxyhydroquinone tetra sodium diphosphate.CBHEOr'PsNan 2,6-dimethoxyhydroquinone tetra sodium diplrosphate.CsHeO4Cl 4-chloro-3,6-dimethoxytoluquinone-2,5; m.p. 134.5-135'.CeHeOsCl 3-chloro-2,5,G-trimethoxybenzoquinone-1,4; m.p. 47-49".C0Hr0O5 tr imethoxybenzoquinone-1,4;  m.p.  160-16lo.CeHirOaNscl 4-chloro-3,6-bis-methylamino-toluquinone-2,5; m.p. > 360'.Cr lHrsO4NzCl 4-chloro-3,6-bis-oxyethylamino-to luquinone-2,5;m.p.195.b-196.5 ' .CrrHrsC)6N, 2-methoxy-3,6-bis-oxyethylamino-benzoquinone-1,4;m.p.20 |  -202".CrzH14O6 2-methyl-5-methoxyhydroquinone diacetate; m.p. 127-128".Cr2IJrdO6 2,6-dimethoxyhydroquinonediacetate;  m.p.  L29-I29.5".

Chinonen en chinonderivaten en hun invloed op micro-organismen

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Chinonen en chinonderivaten en hun invloed op micro-organismen

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