September, 1963
AiXTIBA4CTERIAL
HALOMETHYL A R Y L KETONES
5T3
Antibacterial Agents. Some New Halomethyl Aryl Ketones G. CAVALLIKI,’ E. IIIASSARANI,~ D. NARDI,L. MAURI,F. TENCOXI,F. PACCHIANO, ASD P. NASTEGAZZA Medzcznal Chemistry Research Laboratories, Vister, Casatenouo Brianza ( C O I ~ ZZtuly O), Received A p r i l 19, 196s The antibacterial activity of chloroacetyl, dichloroacetyl, and dibromoacetyl derivatives of biphenyl, diphenylmethane, diphenylethane, diphenyl ether, diphenyl sulfide, diphenyl sulfoxide, and diphenyl sulfone was studied. The chloromethyl aryl ketones and the dibromomethyl aryl ketones are active against the Mzcrococcus pyogenes, but their activity is greatly reduced in the presence of sa-um. The dichloromethyl aryl ketones are active against Mycobacterzurn tuberculosas and their activity is not reduced by serum.
TABLE I The dichloroacetamido group of chloramphenicol is essential for the antibacterial activity of this a n t i b i ~ t i c , ~ CHARACTERISTIC ISFRAREU FREQUESCIES‘ and the same group great’ly increases the antitubercuY (C-W lous activity of other parent amino compounds, for Y (C=O) p-disubstitu t e d (OH) phenol -COOH (aromatic), aromatic example, that of 4-aminosalicylic acids4 I n two recent cm.-l cm. ring, mi.-’ patent^,^,^ these observations have been extended to LXI 3460 1706 and 1686 800 mono- and dichloro- and bromomethyl aromatic ke(sharp peak) tones which also exhibit antibacterial activity. I n LXII 3422 1686 8.5 1 continuation of our studies7-10on chemotherapeutically (broad band) active derivatives of biphenyl, diphenyl ether, diphenyl LXIII 3367 1680 s31 sulfide, diphenyl sulfoxide, diphenyl sulfone, and di(broad band) phenylmethane and -ethane, we considered it of interest Infrared spectra were measured in the solid state in K B r to attach mono- and dihalogenoacetyl groups to the 4- pellets with a Perkin-Elmer Model 12C spectrophotometer with KaCl optics. and 4,4’-positions of these ring systems. Such halo ketones are reported in this paper. I n addition, haloacetyl radicals have been attached t’o the 3- and 2,2’TABLE I1 positions of biphenyl, and the 4-positions of 3’-chloroEXPERIMENTAL C O N D I T I O X S FOR FRIEL)EL--CRAP’Tb 3’-methoxy-, 3’,5’-dichloro-4’-methoxy-,and 3’,5’R E ~ C T I O(METHOD M B-1, B-2, B-3) dichloro-4’-hydroxybiphenyl,as well as of 4’-chloroTemp of Reaction diphenyl ether. Compound addition, temp, Time, Chemistry.-Six general methods were employed for no. Method OC. Sol\ e n t OC. hr the preparation of these compounds. Method A inL B-1 10,20 CS* Reflux 6 volves the reaction of a substituted benzoyl chloride B-1 -5,O CS? 5 ) 10 3 TI with diazomet’hane and is convenient for the preparaB-2 -5 C,H,Cl* -5 3 tion of some monochloroacetyl derivatives. Several TI1 B-1 CS, 5,lO 3 -5,O mono- and bischloroacetyl derivatives of biphenyl were I1 B-1 cs, Reflux 6 10,20 were obtained by modified Friedel-Crafts reactions TI11 B-1 CS? 0 6 0 X cs, 5,10 6 B-1 0,5 (methods B-1, B-2, B-3) (for experimental details, see CzHaC1, 5,10 6 0,s B-1 Table 11). The halogeno ketones of diphenyl sulfoxide B-2 C?H,Cl, 0, 5 5 0 and diphenyl sulfone were prepared from the correXI B-1 CS, 20,30 18 10,20 sponding derivatives of diphenyl sulfide by oxidation C,H,CIZ 20,30 2 0,s XT’III B-2 with hydrogen peroxide in acetic acid (method C). XIX B-1 CzHdCl, 20,30 (36 30 The mono- and dibromoacetyl compounds were obXXIII B-1 CSZ Reflux 6 10, 20 t,aiiied from the corresponding acetyl derivatives by XXT’ cs, 5 , 10 (i B-1 0,5 bromination with stoichiometric amounts of bromine SXVII B-3 CzH4CL -10 ti -15 in acetic acid or chloroform solution (method D). SXIX cs, 5, 10 (i 0,5 B-1 Some dichloroacetyl derivatives were prepared from the XXX B-1 CH, 20, 30 18 10, 20 SSXI B-1 cs, eo, 30 0 10,N corresponding acetyl derivatives by chlorination in Y
-1
(1
(1) Deceased. (2) Author t o whom inquir:es should be addressed a t Research Division of Recordati S.p.B., Milan, Italy. (3) W.A . Sexton, Chem. Constitution Bid. Actiuitg, 233 (1952); Chem. Abstr., 47, 1 0 7 4 7 ~(1953). (4) 9. S.Lih, S. Ferng, W. R. Ting, and T. C. Wang, Bull. Chinese Assoc. Adaan. Sci. (Taiwan), 4 , 1 (lQ>G); Chem. Abstr., 61, 14122a (1957). Gregory, U. S. Patent 2,763,692 (September 18, 19561; Chem. Abstr., 61, 442Yc (1957). (6) IT. Gregory. C . 3 . Patent 2,784,137 ( M a r c h 5 , 1957); Chem. Absti., 61, 11384e (19.57). (7) G . Cavallini, Farmaco (Pavia), Ed. S c i . , 10,644 (1955). (8) G. Cavallini and E. Bfassarani, J . M e d . Pharm. Chem., 1, 365 (1959). (9) G. Cavallini. E. hlassarani, D. Nardi, F. Rlagrassi, P. Altucci, G. Loreneutti, and I;. Sapio, i b i d . , 1, 601 (1959). (IO) G. Cavallini, E. Alassarani, I). S a r d i , L. N a u r i , and P. XIantegazza, i b i d . , 4 , 177 (1961).
SXSII
B-1
0
CS2
5,lO
9
acetic acid (method E) or in acetic acid-acetic anhydride solution (method F). The position of the side chain of the compounds obtained by methods B, D, E, and F was determined by oxidation to the corresponding aromatic acids. I n the chlorination of 4-acetyl-3‘-chloro-4‘-methoxybiphenyl (LVIII) and of 4-acety1-4’-hydroxybiphenyl (LIX), the nucleus was also substituted, 4-dichloroacetyl-3’,.5’-dichloro-4’-methoxybiphenyl(XX) and 4dichloroacetyl-3’,5’-dichloro-~’-hydroxybipheiiyl (XXI)
5i1
( U l U j l U ll Ild
I10
TI1 I, II \'
\I \ I1 \'I11 \
\I \\
1,I
Y\ I Y VI1 I, = ligroin; A = ethanol; H = hexane; (1 = cttiyl acetate. Refererice corresponds to literature data for tlie substituted I)mzoic acids obtained b>-oxidation from halometliyl aq.1 ketones. Ethyl ether ' s a y used as solvent. T h e solution of the acid chloride w i s dropped in a t -5" :ind the mixture was saturated with hydrogen chloride at room temperature. d I n this way a partial demethosylTAB1,E
IV
('iiii~j~u~inrl no.
XVIII SSII
SIX
ss XST SSIII
SSI\'
IS\' SSVI SNVII SST'III
SSIS
sss SSSI SSSII
s s S II I SSSI\'
SSSV SSS\'I A = ethanol; I> = acetic acid; W = water, C = ethyl acetate, I = iuoorouyl alcohol, P = benzene; I, = ligroin; 11 = Reference vorresponds to literature data for the substituted tienzoic a('ids obt:tined by oxidation from halometliyl a r j 1 ILPliesane rL
beiiig obtained, respectively. Evidence for these ieactioiis was obtained by oxidizing XX to 3',5'dichloro-4'-methoxybipheiiyl-.2-carboxylic acid (LX) and by oxidiziiig XXI to 3',5'-dichloro-4'-hydroxybiphenyl-4-carboxylic acid (LXI), which could then be methylated with diazomethane to methyl 3',5'-dichloro-4-methoxybiphenyl-4-carhoxylate, n-hich upon saponification gave LX. One of the two nuclear chlorine atoms must h a w eiitered position 3' sirice tlir kctorie X X had already bet311 prepared from +acetyl8 '-chlo~~o-l'-~iicthosybiphc~iyl (LT'III) l 1 aiid hecauw of
the identity of LY with the product of oxidation ailmethylation of XXI. Tlie 5'-position of the secoiid nuclear chlorine atom may be deduced from a cornd parison of its infrared spectra with those of 3'-chloio1'-hydroxybiphenyl-4-carboxylic acid (LXII) aiitl -1'-hydroxyhipheny1-4-carboxylicacid (LXIII). The position of the secoiid chlorine atom ortho to tlw phenolic hydroxyl group is supported also by the infrared absorption of (0-H) nhich. i n LXI, prcswits ii sharp peak a t 3460 cm. I . This contrasts with the, hivader itmiids at lower fr(ywneiosfound in I X I 1. \\ i t t i
ANTIBACTERIAL HALOMETHYL ARYLKETONES
September, 1963
-
-
% Calcd.
C
H
C1
72 88 69 09
4 81 5 02
15 37 13 60
01 03 62 55 73 62
4 10 3 03 5 3.5
24 02 23 08 14 48
03 .56 74 27 68 16
4 39
22 08 13 70 1-1. 37
59.80
3.58
57.04 51.76
5 84 4 49
3.76 3.23
S
25.22 12,X 19.95 12.02 19.10
CI
C
H
11 93
72 85 69.15
4 74 4 75
15 07 13 74
61 23 62 60 73 65
4 01 3 89 5 07
24 10 23 20 14 90
ti3 90 74 38 68 0!J
4 12 3.96 4 33
22 08
60.17
3.04
25.00 13.00 19.90 12.22 19.20
11.34 9.02 10.88 8.63
57. 04 51.91
3.81 3.21
s
9,%" Celcd.
10.80
16
21
e
.4n excess of hydrogen
-
% Found
S
H
63.41
3.80
26.74
3.86
26 79
63 54 49 48
41 65 85 04 51 09
3 3 2 2 2
80 36 76 30 68
26 32 38 40 37
74 27 95 51 71
63.18 54.93 49.70 48.00 51.28
3.69 3.0i 2.80 2.23 2.61
26 32 38 40 37
08 90 90 40 70
51 64 52 65 53 59 53
09 53 33 54 49 80 27
2.68 4 33 3 10 4 81 3 49 3 58 2 87
37 25 36 24 35 25 33
i1 40 33 18 10 22 70
50.96 64 44 51.80 65.70 53.66 53.30
2.45 4.23 3.38 4.63 3.47 3.57 2.66
37 2.5 36 24 35 25 34
21 57 50 18 09 30 00
49 01 56 59 47 08
2 57 3 39 2 46
36 17 23 85 34 75
10.79
49.20 56.73 47.03
2.41 3.20 2.43
3.5 98 23 98 34 41
11.10
51.07
3.66
22 64 21.54
10.25 9.74
51,02
3.37
22 40 21 30
10.50 9.65
43.65
2.17
32 26
Reaction temperature 40".
15
11.49 9.00 10.85 8.86
CI
c
12 22
18 19 20
H
8.52
59,89
Reaction temperature 25".
only one chlorine atom ortho t o OH, and in LXIII, where no chlorine atoms are present. The intramolecular hydrogen bonding between OH and the two o-chlorine atoms in LXI does not permit intermolecular hydrogen bonding which is responsible for the displacement and broadening of the bands to lower frequencies (see LXIII).
Experimental' 4-Chloroacetyl-4'-methoxybiphenyl(Method A).-To 250 ml. of an ethereal solution of diazomethane, prepared from 25 g. of nitrosomethylurea, 6.15 g. (0.025 mole) of 4'-methoxyhiphenyl( 1 4 ) .\I1 iiielting points end builiiig ,joints are corrected.
e
Ref.b
13 91 14 i 2
C
tones.
CHIO
17
ation occurs. For that reason the purification was difficult and several crystallizations were necessary. peroxide was used.
c
-
% Found
7
CH30
10 51
575
c1
CH80
Ref.b
22
16 8.10 23 24 17 18 19 25 20 21 26 27 28
27 28
An excess of hydrogen peroxide was used. (15) JV. 9. Johnson, D. Gutsche, and R . D. Offenhauer, J . Am. Chem.
S o c , 68, 1648 (1946).
(16) G. W. Gray, B. Jones, and F. Rlarson, J . Chem. SOC.,393 (1957). (17) N. Moses, Ber., 3 3 , 2627 (1900). (18) B1. Schopff, ibid., 27, 2326 (1894). (19) G. Cavallini, E. Massarani, D. S a r d i , L. Mauri, P. Afantegazza, and F. Barzaghi, J . A m . Chem. Soc., 81, 2564 (1959). ( 2 0 ) P. Griess, Ber., 21, 980 (1888). 121) R. Geigy, B . G. Swiss Patent 214,901 (April 1, 1942). (22) R. Symons and Th. Zincke, Ann., 171, 122 (1874). ( 2 3 ) M. Weiler, Ber., 32, 1061 (1899). (24) R. Fittig, Ann., 193, 116 (1879). ( 2 5 ) C. Fischer and R. Wolffenstein, Ber., 37, 3215 (1904). (26) 0. V. Schickh, i b i d . , 69, 242 (1936). (27) A . Michael and .\. Adair, ibid., 11, 119 (1878). ( 2 8 ) A. Michael and A. Adair, iCnd., 11, 121 (1878).
5ici
I:
1) = :icetic, acid; U = aceti,ne: \\ = water; A = etiia~iol; 1' -= 1)enzene; .\I =- irietlianol; ( ~ = ' ethyl acetate. corresponds t o literature d:rt:t for tlie substituted benzoic :icids obtained by oxitl:ition f w n i halonietliyl aryl ketones. 'I
i~:trI)onylrhloride, dissc~lvetlin 250 1111. I J anhydrous ~ benzene, \vas :itlded tlropivise a t 20". -4ft)er 48 lir. :it 20°, the soliition w:ts wtiiratcti ivith :tnhydrous hydrogen chloride, concentrated under rediicwf pressure until crystaIlizatii)n began, and cooled. Thr 1)rc~diii.t\vas filtvred off ~ i n drecrystiilliat.d from ligroin (see Tatil~
Ill'. 3 -C~hloro-4-chloroacetyl-4'-methoxybiphenyl (111 (Method E-1i.~~-C~iloro:ii~etyl i~~i~iiride (11.2 g,, 0.1 niok'i \viis :tdded dropiviw :it 10-20c to :I stirred niisture I C 21.55 g. (0.1 mole) ~i 3r~lil(JrrJ-4-rriet~iosybiphenyl, 100 nil. of anhydrous carbon disulfide, :iiiil 13.3 g. (0.1 mole) of aluniiiiuni chloride. After stirring and rrfiiising for 6 hr., the reaction iiiiiture was poured into ice\\ iitrr i i i i i l :icidifird x i t h hydriwhloric :wid, :ind the crude produrt :IS v \ t ratted n-ith niethylene i.hloridc. ivashed, dried, and frac-
,.
tioi1:itcd.
1 he J.ielcls, clic~tiiiixl:tiit1 p l i j $ i d cl:it:i> :itid :in;ilyscs of thip siihrt i i n ! ~:nit1 o f thc otlicr protiiic+s 1)rep:ireti I Jt h~ i s niet.Iiotl ;ire listptl in T d ~ l e sI11 nnd I\'. Tlir S i d V e I l t , the teniperaiurt.. : i i r < l the1 t inie of reaction of other 1iroducts prep:ired by this are listed in Table 11. 4-Chloroacetyldiphenylmethane (VI) (Method B-2 I.---Ainistitre. of 33.6 g. (0.2 mole) of dipheriylirietliaiie, 100 nil. of ethylerie. :ind 22.6 g. (0.2 inole: of chloroacetyl chloride was added i,liloridc~, dropwise ut -5' Tvith stirring to a mixture of 26.6 g. (0.2 mole) of iilriniinririi chloride and 100 nil. of ethylene chloride. After stirring :it -5' for 3 1-11.. the mixture \vas poured into ice-water, :ic*itiifictl~ 4 t hhydroc~hloricacid, separated, and the water layer \\.:is estr:icted ivith et,hylene rhloride. The extrarts xwre washed wit li \ v : i t w . .\fter drying and cwncwntration, the residue \\-as tlistillcil :it rediicwl pressure. The yields, chemical arid physical i!:ita, :mil :tn:iiyses of this subst:inctl and of the other produrts l)rcil):ired by this niethotl are listed in Tables TI1 and IV. 4-Dichloroacetyldiphenylethane (XXVII) (Method B-3). I>ic~lil~iro:ic.rtyl rliloridc ( 1 4.74 g., 0.1 mole) was added dropwisc i\ith .stirriiig :it 20' t o n mixture of 16.07 g. (0.125 mole) of aliri r i i i r i i i r i c.liloride m i l 50 nil. of ethj.lene chloride. Stirring a t 20" 1v:is i,~)ntinued l'or 30 niin., tlict sr~hitiorr!viis decanted from i i l i t r i i i i i i i i i i chloride :rnd added, at - 15", t o :t solutioii iif 1 tript h i d
"
Iteferenw Reaction
(0.1 t i i i ~ l ~0 1 tlil,li(:iiyletliatie in 50 nil. of rtliylene i~hloritlc~. After stirring the m i c t i o n inistiire :it - 10' for 6 hr., it ~ v i t s poured into ivnter ant1 v - o r k d iip :is usu:il. l:or d:it:t, see 'V:iI)lc~
I\.. 4-Chloroacetyldiphenyl Sulfoxide ( X V ) (Method C',. ----'Po ; i solution of 5.24 g. (0.02 niolc? of' l-cliJc~roai~t.t~ldiplien~-l sulfide i r i 100 nil. of glaci:il :ir.c.t.ic' :icd nits :dded 2.38 1111. (0.02 niolej of 30(, hydrogel1 pcroiidt:. After rt:inding :it, ~I)IIIII teniprr:itiirc~ for 48 hr.; the niirturc \v;is poured into 2 1. of ice-w:iter. :inti tht, product v a s filtered off :ind c-rystallized (see Tables 111 and I V 1. General Directions for iMono- and Dibromoacetyl Derivatives (Method Dj.-To :i solution of 0.1 niole of the aryl niethyl IxAorir~ in (a) glacial acetic :rc,iti or (I))chlorofornlj the required a n i i ~ ~ i n t , of bromine \vas ndtled : i t 30-40' :md t h e inixture \viis btirrtd until the d i r dis:tppcwwl. \Yheii ac.c,tic w:ts :tddeti t o prciipit:i tt> thr. prodiic,t, \vhicb K:+S filtered, a~:~sIirtl with water, : ~ n dcryst:tllizetl or distilled. If the rtx:ic,ticiri \\:is c,arried out in c~hlori,fornr. tho solution \vim w:islied \I it11 \\:itcxr. dried, evaporatetl, nnd the residue c.rystallized E ~ O I I I :I s i i i t : i l ~ I i ~ solvent (see Tables lr :ind IT). 4-Dichloroacetylbiphenyl(XVIII) (Method Ej.--A S I J I ~ I I ~ I $~ Ii fI 19.r; g. (0.1 niolej i ~ fI-acetylbiphenyl in 250 nil. of ;ic,etic ai,id. \v:trnied a t BO", \nis s:ituriited \vith a stream of chloririt~. Xitrogen w t s bubbled i n i o remove excess chlorine and hydroptw chloride, and the 4-dichloroacet.ylbipheny1 crystallized O I ~d t l i tion of natcr. I t \viis filtered, rvashed, and recrystallized (sr(' Table IV j. 4,4'-Bis-(dichloroacetyl)diphenyl Sulfide jXXXIIIj (Method F I .--A stream of i'hlorine and nitrogen W B S passed throuyh :I S I d U ~ i l J of ~ i 27 g. (0.1 rriole) of 4,4'-bis(acetyldip}len~~l) sulfide itr 250 rnl. of glai,i:il :iceti(':tiid arid \T.arined itt 60" until the solutioti \vas saturated \ T i t t i chlorine. It \vas cooled, and the product, lvhicfh crystallized, \v:is filtered. washed with waterj and recrystallized (see Table IV,. 3',5'-Dichloro-4'-hydroxybiphenyl-4-carboxylic Acid (121;. A si~liiti~ii of 3.5 g. (0.01 mole) of I-diclilr~rc~ni~~tyl-3',5'-di1~lili~r~ I~ ' - h ~ ~ d r o s ~ l ~ i(SSI) ~ ~ l i eirir i20 ~ l1111. of ~lios:iticw i s refl~ixcdf o r 5 t i r . ~vitliii soli1tii~11 01' 3 . I r i g. (0.02 niole's of potassiuni ~ J P ~ T I ; L I I -
September, 1963
-
% Calcd. C
H
til, 11
4.03 3.02 3.05 3.27 2.63
45.79 49.51 49.56 41.76
577
ANTIBACTERIBL HSLOMETHYL ARYL K E T O N E S
Br
29.05 21.76 40.35 23.56 34.73
N
6
- -
7.67 6.97
Found
H
C
60.67 46.00 49.16 49.31 41.39
3.75 2.62 3.15 3.27 2.56
Br
29.11 21.99 40.07 23.90 35.28
N
S
-
Rei.6
29 30 23
7.50 6.94
27 28
substituted benzoic acids obtained by oxidation from halomethyl aryl ketones.
% ' Calcd. Br
C
H
47 48
2.84 1.81
45.14 35,99
34 6!) 34 60 48 94 35 95
1.82 1.82 3.29
5i.71
j0 29
3.69 2.42 2.72 1.ii
37.86
37 15 4.5 43 33,72 43.5.5 3 2 . 79
40.21 31.09
2.13
R Found N
G ,31
57.71
43,42 56.29 41.83 54,93 43.19 56.09
2 61
41.40
1.72 2.41 1.63
*54.5,;
38.23 51.73
C
S
3.18
H
Br
47 61 38 19
2 88
45.36
1.94
35.90
34 G8 34 68 49 19 36 12 50 85 37 54 4.5 68 33 96
1 .il 1 ,ti3 3 41 1.97 3 81 2.45 2.66 2.04
57.62 5 7 .94 43.19 56.19 41.44 54.78 1 " 59
43 37 33 33 40 3.5 31 43
2 G4
41 .39
1.51
54.48 38.09 51,60
2.62 1.45
N
S
Ref.
22 30
6.18
23 24 17 18 19 25 20 26
55.54
27 28 27 5.30
28
temperature 80-90"
ganate in 40 ml. of 127, aqueous sodium hydroxide. After filtration from manganese dioxide, the precipitate, formed on acidification with hydrochloric acid, was recrystallized from acetic acid to give 2.7 g. (95%) of 3',5'-dichloro-4'-hydroxybiphenyl-4carboxylic acid, m.p. >300". A n a l . Calcd. for C13H8C1203: C, 55.15; H, 2.85. Found: C,54 58; H, 2.72. 3',5'-Dichloro-4'-methoxybiphenyl-4-carboxylic Acid (LX). (a).-A similar oxidation of the 4-dichloroacetyl-3',5'-dichloro4'-methoxybiphenyl (XX) afforded a 90% yield of 3',5'-dichloro4'-methoxybiphenyl-4-carboxylic acid (LX) which crystallized from acetic acid, m.p. 210". A n a l . Calcd. for Cl4H&IZO3: C, 56.61;H, 3.39;C1, 23.88. Found: C, 56.64;H, 3.43;C1, 24.18. (b).-To a well stirred solution of 2.83 g. (0.01mole) of 3',5'dichloro-4'-hydroxybiphenyl-4-carboxylic acid (LXI) in ether, cooled a t 5", a solution of 0.88g. (0.02mole) of diazomethane in 40 ml. of ethyl ether was added dropwise. After 5 hr. standing at 5-8" the 3',5'-dichloro-4'-methoxybiphenyl-4-carboxylic acid (LX) crystallized and was recrystallized from acetic acid, yield 2.08 g. (707,);m.p. 210-211'. A n a l . Calcd. for C14HIOC1203: C, 56.61;H, 3.39; C1, 23.88; CH30, 10.44. Found: C, 55.81; H , 3.23;C1,24.01; CHaO, 10.15. Microbiology.-The antimicrobial activity of all compounds was tested in oztro by the usual procedures of the tube dilution method. I n Table VI1 the minimal inhibiting concentrations are reported for Mzcrococccus pyogenes var. aureus, Salmonella typhi, and Mycobacterzum tuberculoszs H 37 RV. For the tests 1% solutions in Carbowax were prepared. These solutions were then diluted with media to make a concentration of 100 y/mL The inoculum was 0.1ml. of an 18-hr. broth culture (1: 100) of M . pyogenes or S . typhi, or 0.1 ml. of a 7-day broth culture of ~21.tzrberculoszs. The incubation temperature wa€ 37". (29) P.Jacobson, Ber., 28, 2547 (1895). ( 3 0 ) H. Strasser and G. Pcliults, Ann., 210, 191 (1881). (31) A. Collet, Bull. SOC.Chtm. France, (3)17,510 (1897). (32) B. R. Carpenter a n d E. E. T u r n e r , J . Chem. Soc., 869 (1934).
Results and Discussion Table VI1 records the results of antibacterial screening. As can be seen from these data, the monochloromethyl aryl ketones tested clearly show activity against X . pyogenes var. aurezis which , however, decreases in the presence of serum. Some of these substances are weakly active against 5'. t y p h i . Almost all of them also have slight activity against M. tuberculosis in the presence of serum. The chloroinethyl ketones were not screened because of their irritating properties. The dichloromethyl aryl ketones are slightly active against M . pyogenes Tar. aui eus, and inactive against S. t y p h i , but show considerable inhibitory activity against 34. tuberculosis in the presence of serum. The corresponding dibromomethyl aryl ketones are less active against *VI. tuberculosis than their dichloromethyl analogs, but they show slight activity against X. t y p h i and good activity against A f . pyogenes; this latter activity is, however, reduced by serum. The 2,2'disubstituted derivatives of biphenyl are practically devoid of antibacterial activity. ,4s in a series of guanylhydrazones10previously tested, the 4,4'-disubstituted derivatives of biphenyl, diphenylethane, diphenyl ether, and diphenyl sulfide exhibited ( 3 3 ) C . F a l t e r and J. Ross, {bid., 538 (1945). (34) F. Kunekell, K. Eros. E. Muller, and A. Hindebrandt, Ber., 23, 188 (19 13). ( 3 5 ) 13. H. Szmant a n d F. P. Palopoli, J . A m . Chem. Soc., 71, 1756 (1950). ( 3 6 ) 31. Tomita, H. I 6.25 :i, I2 6.25 100 100 0 0
10(1 23 50 0
I1
50 (I
;.
12.5 0
I1 I)
ll
9 r,.-
50 100
100
\ftf.I 24 111
2 .j 2*-) 2;. I 2 ,-, 50 25 30 50 .iO
2.3 ?,-I
1)
(I
IO0 100 100 50 2,; 0 0 2.i 0 12 3 il 100 25 0 12 ;. .50
50 50 2.i -.'> j I uo 2.-, 1;. 25 12.5 6 2.5 3 12 3.12 30 1.56 1.56 25 23 50 1 .SG 100 1.56 (i2.i 1.56 1.56 100 I .56 1.56 ::, 12 100 ti, 25 100 I .50 I .5ti 100 I .5G 1.56 3.12 :j,12 100 3.12 100 I .36 3 12 100 6.25 6 . 2.5 12 5 100 Slrdiuin: IXfw nutrient broth 19; Tween 80. Medium: Difco nutrient broth I?&Tween 80 IO$/; beef seriixii. %ICdiuiit: Ihfco Ilubos broth base IO%'Bacto Dubos medium serum. 4-Chloroacetylbiphenyl, see ref. 31. 6 The nuniher zero indirate3 no nctivity under 100 pg./nil. f 4,4'-Bis(chloroacetyl)biphenyl, see ref. 32. 1,4'-Bis-~hloroacetyldiphenylethane,see ref. M . * .l,.l'-Ris(chlorowetyl)diphenylether, see ref. 34. 4-Chloroacetyldiphenyl sulfide, see ref. 35. 3 4,4' -Bis(chloroacet~l)diph~ri~l YUIfide, see ref. 36. ,?(I
2;,
+
+
the highest aiitihacterial activities, pointing to thc signihcance of these "supporting" molecular moieties. Acknowledgment.-We wish to thank Prof. >I.
+
+
Keggiaiii a i d Lh.€3. Casu of the lstitiito Itotizoiii of Milan for their cooperation i l l c4arrying: out atit1 i l l terpreting the iiifrared spectra.
