Synthesis, Structural Stability Calculation, and Antibacterial Evaluation of Novel 3,5-Diphenylcyclohex-2-en-1-one Derivatives

Article abstract of DOI:10.1080/00397911.2014.994128

(Chemical Equation Presented). Starting with 3,5-diphenylcyclohex-2-en-1-one, 3,5-diphenylcyclohex-2-en-1-semicarbazone, 1-chloro-3,5-diphenylcyclohex-2-en-2-carbaldehyde, and 3,5-diphenylcyclohex-2-en-1-hydrazone were synthesized via the reactions with s

Full text of DOI:10.1080/00397911.2014.994128

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Synthesis, Structural Stability Calculation
and Antibacterial Evaluation of Novel 3,5-
Diphenylcyclohex-2-en-1-one Derivatives
Omyma A. Allah Abda, Ahmed M. El-Saghiera & Asmaa M. Kadrya
a Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
Accepted author version posted online: 23 Dec 2014.
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To cite this article: Omyma A. Allah Abd, Ahmed M. El-Saghier & Asmaa M. Kadry (2014): Synthesis, Structural Stability
Calculation and Antibacterial Evaluation of Novel 3,5- Diphenylcyclohex-2-en-1-one Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.994128
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SYNTHESIS, STRUCTURAL STABILITY CALCULATION AND
ANTIBACTERIAL EVALUATION OF NOVEL 3,5- DIPHENYLCYCLOHEX-2-
EN-1-ONE DERIVATIVES
Omyma A. Abd Allah,1 Ahmed M. El-Saghier,1 Asmaa M. Kadry1
1Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
Abstract
Starting with 3,5-diphenylcyclohex-2-en-1-one, 3,5-diphenylcyclohex-2-en-1-
semicarbazone; 1-chloro-3,5-diphenylcyclohex-2-en-2-carbaldehyde and 3,5-
diphenylcyclohex-2-en-1-hydrazone were synthesized via the reactions with
semicarbazide hydrochloride; POCl3 / DMF and hydrazine hydrate, respectively. These
products were used as key intermediates for the preparation of novel series of
tetrahydrobenzothiadiazol-1-oxide, indazole, benzo- thiazepines, pentahydroxyhexylidene
and N-thiazines. Some of these derivatives exhibit highly antibacterial activity against
gram positive bacteria.
KEYWORDS: diphenylcyclohexenone, tetrahydrobenzothiazepine, thiazolidinone,
indazole, pentahydroxyhexylidene, antibacterial.
INTRODUCTION
Cyclohexenones are efficient synthons in building spiranic compounds1 or intermediates
in the synthesis of fused heterocyclic derivatives. Ethyl-3,5-diarylcyclohexenone-6-
carboxylate has been used as an effective synthon in some projected synthesis of spiro
cyclo- hexanones7and carbazol derivatives8. Allylic oxidation of olefins to α, β-
1

unsaturated ketones, particularly cyclohexene to cyclohexenone, is an important and
useful transformation in both chemical and pharmaceutical industries2-6, since α,β-
unsaturated ketones were used as herbicides and employed in the construction of a wide
variety of biologically and medicinally important products. From this point of view and
extending our previous work on the preparation of azolo compounds9- 14 we tackled this
work to fuse cyclohexenone moiety with well-known pharmacophoric moieties of
potential anti-microbal activities such as thiadiazole15, pyrazole, isoxazole16, thiazepine
or carbazole rings17and evaluate the anti-bacterial activity of some of these derivatives.
RESULTS AND DISCUSSION
The parent compound 3,5-diphenylcyclohex-2-en-1-one (1) can be prepared according
to the literature in fairly good yield by decarboxylation of 6-carbethoxy-3,5-diphenyl-
cyclohex-2-en-1-one under either acidic or basic conditions18,19 and has been used as
an effective synthon by Padmavathi et al. for the synthesis of a range of heterocyclic
derivatives16.
In this study, compound 1 was reacted with semicarbazide hydrochloride/sodium acetate
in refluxing ethanol to give 3,5-diphenylcyclohex-2-en-1-semicarbazone (2) (Scheme 1).
-1
Its IR spectrum showed new signals at 3555, 3458 and 3200 cm attributing to NH2 and
NH groups. Its Mass spectrum analysis showed the molecular ion peak at m/z = 305(M+)
of the molecular formula C19H19ON3.
2

Regarding to the reactivity of the methylene and the semicarbazone groups of compound
2, its treatment with thionylchloride in CH2Cl2 or phosphursoxy chloride in DMF 20
(Vilsmeier- reagent) afforded 5,7-diphenyl-2,6,7,7a-tetrahydrobenzo [d][1,2,3]
thiadiazol-1-oxide (3) and 3-carbaldehyde-4,6-diphenyl-2,3,3a,4,5,7a-hexahydro-2H-
indazole (4), respectively (Scheme 1). IR spectra of compounds 3 and 4 pointed to the
absence of the bands corresponding to the amino (NH2) group, while showed the
-1
presence of new bands at 3462 and 1019 cm assigned to NH and S=O groups in
-1
compound 3 and at 3454, 3403, 1682 cm assigned to 2NH and C=O groups in
compound 4. Mass spectral analysis revealed the molecular ion peaks of compounds 3
and 4 at m/z = 308.3(M+) and m/z = 304(M+), corresponding to the molecular weight of
the molecular formula C18H16N2OS and C20H20N2O respectively. Spectral analyses of
these compounds were consistent with the proposed structures.
The relative stability of tautomeric structures of compound 4 and its relation with
compound 1 have been conducted through using 3D modeling procedure. The structures
were fully optimized using Gaussian03 package with density functional theory (DFT)
method, at B3LYP level of approximation. Calculations were carried out with 6-311G (d,
p) basis set21, 22
.
The investigation of the electronic structure at highest occupied molecular orbital
(HOMO) and lowest unoccupied molecular orbital (LUMO) positions shows the location
of the active site. The difference between the energy of HOMO and LUMO positions was
calculated to give the energy gap of compound 1 compared with the energy gap of each
3

tautomeric structures of compound 4. This confirmed that the compound 4 is more stable
than compound 1 and tautomer 4a is more stable than 4b by -38.65 kcal / mol ( Table 1)
ensuring the existing of the reaction with the stable product of low energy. Another
evidence of its stability appears from larger chemical hardness η in addition to its high
energy gap ΔE (Table 2). So, the spectral analyses are constituent with the theoretical
analyses23.
The presence of the active methylene group (O=C-CH2) in compound 1 leads to its
condensation reaction with thiourea / I2 in refluxing isopropanol to form 5,7-Diphenyl-
6,7-dihydro-2(3H)-imino-1,3-benzo[d]thiazole (5) in a good yield (Scheme 2). IR
spectrum revealed disappearance of the C=O group and the appearance of two bands at
-1
3383 and 3297cm for 2NH groups. Its mass spectrum showed a molecular ion peak at
m/z = 303(M+-1) corresponding to the molecular weight minus one of the molecular
formula C19H16N2S.
4

2-Chloro-4,6-diphenylcyclohex-2,4-diene-1-carbaldehyde (6) was prepared in a
good yield (60 %) under Vilsmeier condition through the reaction of compound 1 with
POCl3 in boiling DMF (Scheme 2). The structure of compound 6 was confirmed on the
bases of their spectral data. The IR spectrum of compound 6 showed the presence of new
-1
bands at 1743 and 757cm ,indicating the presence of C=O and C-Cl groups
respectively.
Compound 6 was used as an intermediate for the preparation of a new series of
polyfused heterocyclic derivatives. In this work the reactivity of the Cl and CHO groups
in compound 6 toward the condensation reactions with the bidentates was investigated.
Thus when 2-chloro-cyclohexadiene-1-carbaldehyde derivative 6 was treated with
hydrazine hydrate, ethylene diamine and /or cystamine hydrochloride, it formed the
corresponding fused heterocyclic compounds, namely 4,6- diphenyl- 4,5-dihydro-1H-
indazole (7), 6,8-diphenyl-2,3,4,6-tetra- hydro-1H-benzo[1,4-e] diazepine (8) and 6,8-
diphenyl-2,3,4,6-tetrahydro-1H-benzo[1,4- f] thiazepine (9) (sheme 2). These reactions
took place via the initial nucleophilic displacement of the chloride ion with the amino
group in hydrazine hydrate and ethylene diamine molecules or with SH group in
cystamine hydrochloride molecule. The formed intermediates in situ were cyclized by the
condensation reaction of the reset amino group with the aldehyde group. IR spectral data
-1
of compounds 7- 9 showed that there were no bands at 1743 and 757 cm for C=O and
C-Cl groups.
5

Finally, compound 6 was allowed to react with ethyl mercaptoacetate upon boiling in
ethanolic sod.ethoxide solution to afford 4,6-diphenyl-5,6-dihydrobenzo[b]thiophene
derivative (10) through the nucleophilic displacement of the chloride ion with the SH
group as in the previous mechanism. The formed intermediate underwent intramolecular
cyclization reaction via the condensation reaction of the active methylene group with
aldehyde group (Scheme 2). Spectral analyses of these compounds as in the experimental
section confirmed the suggested structures.
3,5-Diphenylcyclohex-2-en-1-hydrazone (11) was formed according the
literature24 through the condensation reaction of compound 1 with hydrazine hydrate.
The formed hydrazone derivative was used as a key intermediate for the preparation of
2E-(3,5-diphenylcyclohex-2-en-1-ylidene)hydrazene-N'[(2R,3R,4R,5R)-2,3,4,5,6-
pentahydroxyhexyl- idene (12) and (3,5-diphenylcyclohex-2-en-1-ylidene)hydrazene-N’-
(4-nitrobenzylidene) (13) via its condensation reaction with both of the D(+) glucose in
boiling DMF or 4-nitro- benzaldehyde in refluxing glacial acetic acid with the
elimination of water molecules (Scheme 4). The structures of compounds 12 and 13 were
verified by spectroscopic data. For example, the IR spectra of these products revealed the
lack of the amino group (NH2) and the appearance of characteristic bands at 3433, 1637
-1
cm pointed to OH, N-H, C=N groups of compound 12, and at 1518, 1339 cm
-1
attributed to NO2 group of compound 13. These results revealed that the hydrazone
derivative 11 reacted with –CHO group of both of D(+)glucose and 4-nitrobenzaldehyde
molecules.
6

Compound 13 was reacted with thioglycolic acid in boiling dry benzene to afford
3-(3, 5-diphenylcyclohexa-1,5-dienylamino)-2-(4-nitrophenyl)-1,3-thiazolidin-4-one (14)
through the nucleophilic addition reaction of thioglycolic acid at the (Ar-CH=N-) group
of compound 13. The formed intermediate spontaneously was cyclized via the
elimination of water molecule where the structure of the product was supported by
spectroscopic data (Scheme 3).
On the other hand, the nucleophilic addition reaction of 3,5-diphenylcyclohex-2-en-1-
hydrazone (11) at phenylisothiocyanate took place in a new experimental method in
refluxing dioxane furnished the functionalized thiosemicarbazied derivative24 15 which
in turn used for the preparation of N- thiazole and N-thiazine derivatives 16, 17 via the
cyclization reaction with chloroacetyl chloride or malonyldichloride in refluxing DMF
and triethylamine (Scheme 4). IR spectrum of compound 16 showed two new bands at
3359 and 3155 cm-1 resulting from the presence of the hydroxyl (OH) and imino (NH)
groups. Also, 1H-NMR data displayed singlet signals at δ 4.23 and 8.95 ppm for CH- and
OH groups of N-thiazole ring point to the formation of the totumer forms -COCH2 ↔
HOC=CH, whereas IR spectrum of compound 17 showed the new bands at 3407 and
1733 cm-1 ascertaining the presence of OH and C=O groups.
Alkylation reaction of compound 11 with ethyl bromoacetate in boiling dioxane and
triethyl amine afforded ethyl 2-[2-(3,5-diphenylcyclohex-2-en-1-
ylidene)hydrazinoacetate (18) in a moderate yield. The suggested mechanism path way as
shown in Scheme 5 took place via the hydrolysis of some hydrazone molecules with HBr
7

resulted from the reaction of the formed (Et)3N+.HBr- with water forming hydrazine
molecules.Then, hydrazine molecules reduced C=N group in the synthesized
hydrazoacetoacetate derivative to afford compound 18. The later could be easily
converted to 2-[2-(3,5-diphenylcyclohex-2-en-1-ylidene)hydrazino] acetohydrazide(19)
upon boiling in ethanolic solution of hydrazine hydrate (Scheme 4). The chemical
structures of compounds 18 and 19 were established on the basis of their spectral data.
The reaction of hydrazied derivative 19 with acetylacetone in refluxing ethanolic solution
furnished the functionalized pyrazole derivative 20 (Scheme 5). The spectral analyses of
the latter product pointed to the formation of the suggested structure.
EXPERIMENTAL
All melting points are uncorrected and were determined by Kofeler melting point
apparatus. IR (cm-1) spectra were recorded (KBr disc) on a Shimadzu DR-8001
spectrophotometer. 1H-NMR (DMSO-d6 or CDCl3) spectra were recorded at 400 MHz on
a Varian Gemini NMR spectrometer and also 400 MHz on a Varian Mercury- 300 BB at
Sohag University, the chemical shift is expressed in δ value (ppm) using TMS as an
internal reference. Mass spectra were performed on Micro mass 7070 E`1spectrometer
using Direct Inlet and Shimadzu Qp-2010 Plus mass spectrometer using Electronic
Ionization mode operating at 70 ev.
Synthesis Of 3,5-Diphenylcyclohex-2-En-1-Semicarbazone (2)
To a solution of semicarbazide hydrochloride (6.0 g, 0.05 mol) and sodium acetate (9.0 g,
0.1 mol) in 30 ml of water, a solution of 3,5-diphenylcyclohex-2-en-1-one (1) (12.4 g,
8

0.05 mol), in ethanol (200 ml) was added. The reaction mixture was refluxed for 4 hrs,
after cooling the semicarbazone product was separated, filtered off and crystallized from
ethanol as white fine powder ; yield: 96%; mp 187-189ºC; IR (λ max,cm-1): 3555-
3458(NH2), 3200(NH), 3044(CH arom) , 2924(CH aliphatic), 1674 (C=O) , 1562 (C=N),1438
(C=C); 1H-NMR (DMSO-d6), δ ppm: 9.36(s,1H,NH, disappeared by D2O) ,7.55-7.25
(m,10H,CHarom.), 6.67(s, 1H, CH oliph.), 6.34 (s, 2H, NH2, disappeared by D2O),5.85 (s,
1H,NH, disappeared by D2O), 3.16-3.14 (d,1H, CH=C), 3.02-2.98(d,2H,CH2), 2.81-
2.77(m,1H,CH-Ph); MS (m/z,I%): 305(M+), 304.6 (20.9) (M+-
1),261.8(17.8),246(25.6),215(24.0),203(11.6),143(28.7),117(20.2),105(30.2),91(100.0),
77 (31.8), calc. for C19H19ON3(M. wt = 305).
Synthesis Of 5,7-Diphenyl-2,6,7,7a-Tetrahydrobenzo[D][1,2,3]Thiadiazol-1-Oxide
(3)
Freshly distilled thionyl chloride (8 ml ) was taken to a round bottom flask (50 ml) placed
in a salt-ice bath at about -10 oC, 3,5-diphenylcyclohex-2-en-1-semicarbazone (2) (3.05g,
0.01 mol) was added in three portions maintaining temperature between 0 oC and -10 oC.
After complete addition, the reaction mixture was allowed to stand at room temperature,
25 ml of dichloromethane was added and the mixture was stirred for another 2 hrs.
Excess thionyl chloride was decomposed by slowly adding sodium carbonate solution
(15-20 ml) to the reaction mixture , the organic layer was separated, washed thoroughly
with water, sodium bicarbonate (5%) solution and dried over anhydrous sodium sulphate.
The solvent was evaporated under reduced pressure , the separated solid was filtered off
and crystallized from water as pale green fine powder.
9

Synthesis Of 4,6-Diphenyl-2,4-Dihydro-1H-Indazole-3-Carbaldehyde (4)
A mixture of DMF (2.3 ml, 0.3 mole) and POCl3 (2.8 ml, 0.3 mole) was stirred at 0 oC
for 10 min, a solution of the 3,5-diphenylcyclohex-2-en-1-semicarbazone (2) (3.05 g,0.1
mol) in DMF (10 ml) was added drop wise. The reaction mixture was stirred at room
temperature for 1 hrs and then heated at 70 oC for 4 hrs. After cooling at room
temperature, the mixture was neutralized with cold potassium carbonate solution. The
separated solid was filtered off, washed with water, dried and crystallized from ethanol as
yellow crystal.
Synthesis Of 5,7-Diphenyl-6,7-Dihydro-2(3H)-Imino-1,3-Benzo[D]Thiazol (5)
To a solution of 3,5-diphenylcyclohex-2-en-1-one (1) (0.39 g, 0.0015 mol) and thiourea
(0.11 g, 0.0015 mol) in isopropanol (40 ml), iodine (0.25 g, 0.002 mol) was added. The
reaction mixture was refluxed for 6-8 hrs. The excess of the solvent was removed under
reduced pressure, aqueous NaHCO3 solution was added and the obtained semisolid was
extracted with ether. The ether layer was washed thoroughly with water, dried over
anhydrous Na2SO4, evaporate and the separated solid was collected as yellow crystal.
Synthesis Of 2-Chloro-4,6-Diphenylcyclohexa-2,4-Diene-1-Carbaldehye (6)
To a solution of 3,5-diphenylcyclohex-2-en-1-one (1) (2.48 g, 0.01 mol) in dry DMF (20
ml), a solution of phosphorusoxychloride POCl3 (4.10 g, 0.03 mole) in
dimethylformamide (30 ml) was added drop wise with stirring for 1hrs. at 0 OC. The
reaction mixture was then stirred for an additional 4 hrs at 70 OC. After cooling, the
10

mixture neutralized with cold potassium carbonate solution, the precipitate was filtered
off, washed with water and crystallized from dioxane as yellow crystal; yield: 47%; mp
169-170ºC; the molecular formula C19H15OCl (mol. Wt.= 294.5); IR (λ max, cm-1):
3043(CH arom.), 2940(CH aliphatic), 1743(CHO), 1602 (C=C),757(C-Cl); 1H-NMR(DMSO-
d6), δ ppm: 7.71(s,1H,CHO), 7.70-7.24(m, 10H, CHarom. ) , 6.46 (s,1H, CH oliph.),3.02-
3.01(d,1H,CH-CHO), 2.84-2.76(m, 1H, CH-Ph),2.56-2.55(d, 1H, CH=);13C-NMR
(DMSO-d6),δ ppm: 34.74(CH=), 35.73(CH-ph), 44.06 (CH-CHO), 124.66
(CHoliph.),126.83-138.5(C of Ph),144.21(C-Ph), 159.12 (C-Cl), 198.8 (CHO); MS (m/z,
I%): 293.8(20.0)(M+-1),107.6(20.0),81.2(30.0),59.8(100.0),51.4(20.0),calc.for
C19H15ClO(M. wt.= 294.7) .
Synthesis Of 4,6-Diphenyl-4,5-Dihydro-1H-Indazole (7)
To a solution of compound 6 (2.95g, 0.01 mol) in ethanol (20 ml), hydrazine hydrate
(0.31 ml, 0.015mol) and a catalytic amount of triethyl amine were added. The reaction
mixture was refluxed for 6 hrs. The excess of solvent was evaporated under reduced
pressure , the obtained solid was collected, dried and crystallized from ethanol as yellow
crystal.
Synthesis Of 6,8-Diphenyl-2,3,4,6-Tetrahydro-1H-Benzo[1,4-E] Diazepine (8) And
6,8-Diphenyl -2,3,4,6-Tetrahydro-1H-Benzo[1,4-F] Thiazepine (9)
To a solution of compound 7 (2.95 g, 0.01 mol) in ethanol (20 ml), the proper amine
(ethylenediamine or cystamine hydrochloride) (0.01 mol) and triethyl amine (1.4 ml, 0.01
11

mol) were added. The reaction mixture was refluxed for 6 hrs. The separated product was
filtered off and crystallized from suitable solvent.
Synthesis Of Ethyl 4,6-Diphenyl-4,5-Dihydro-1-Benzo[B]Thiophen-2-Yl-2-
Carboxylate (10)
A mixture of compound 7 (2.95 g, 0.01 mol), ethyl mercaptoacetate (1.096 ml, 0.01 mol)
and sodium ethoxide solution (0.23 g of Na dissolved in 20 ml of ethanol) was refluxed
for 6 hrs. The mixture was concentrated , the formed precipitate was filtered off and
crystallized from ethanol as yellow crystal.
Synthesis Of 2E-(3,5-Diphenylcyclohex-2-En-1-Ylidene)Hydrazene-
N'[(2R,3R,4R,5R)-2,3, 4,5,6–Pentahydroxyhexylidene (12)
To a solution of compound 11 (2.62g, 0.01mol) in dimethylformamide (20 ml), D(+)
glucose (1.80 g, 0.01 mol) and (0.1 ml) acetic acid were added. The mixture was heated
under reflux on a water-bath for 2 hrs. The separated solid on cooling was filtered off
and crystallized from ethanol as pale brown crystal.
Synthesis Of (3,5-Diphenylcyclohex-2-En-1-Ylidene)Hydrazene-N’-(4-
Nitrobenzylidene) (13)
A mixture of compound 5 (2.62 g, 0.01 mol) and p-nitrobenzaldhyde (1.51 g, 0.01 mol)
in glacial acetic acid (20 ml) was refluxed with stirring for 5 hrs. After cooling, the
formed solid was filtered off and recrystallized from ethanol as pale yellow crystal.
12

Synthesis Of 3-(3,5-Diphenylcyclohexa-1,5-Dienylamino)-2-(4-Nitrophenyl)-1,3-
Thia- Zolidin-4-One (14)
Thioglycolic acid (0.69 ml, 0.01mol) was added drop by drop to a solution of compound
13 (3.95g, 0.01mol) in dry benzene (30 ml). The reaction mixture was refluxed for 10 hrs
and the solvent evaporated under reduced pressure. The solid was triturated with
petroleum ether (60-80 OC), filtered off, dried and crystallized from CHCl3/ pet.ether (40-
60 OC) as deep yellow crystal.
Synthesis Of 2-(3,5-Diphenylcyclohex-2-Enylidene)-N-Phenyl Hydrazine
Carbothioamide (15)
A solution of compound 11 (2.62 g, 0.01 mol) and phenylisothiocyanate (0.135 g, 0.01
mol) in dry dioxane (30 ml) was refluxed for 5hrs. The reaction mixture was concentrated
under reduced pressure, the obtained solid was filtered off and recrystallized from
ethanol.
Synthesis Of 3-(3,5-Diphenylcyclohexa-1,5-Dienylamino)-2-Phenyliminothiazolidin-
4-One (16) And 3-(3,5-Diphenyl-Cyclohexa-1,5-Dienylamino)-6-Hydroxy-2-
Phenylimino-2,3-Di- Hydro[1,3] Thiazine-4-One (17)
A mixture of compound 11 (3.97 g, 0.01 mol) and a proper dihalocompounds
(chloroacetyl-chloride or malonyldichloride) (0.01 mol) was refluxed in dry DMF (20 ml)
for 4 hrs. After cooling, the formed solid was filtered off, and recrystallized from the
proper solvent.
13

Synthesis Of Ethyl [(2E)-2-(3,5-Diphenylcyclohex-2-En-1-
Ylidene)Hydrazine]Acetate (18)
To a solution of compound 11 (2.62 g, 0.01 mol) in dioxane (20 ml), ethyl bromoacetate
(1.10 ml, 0.01mol) and triethyl amine (1.4 ml, 0.01mol) were added. The reaction
mixture was refluxed for 6 hrs. After cooling, the separated solid was collected and
crystallized from ethanol as yellow crystal.
Synthesis Of 2-[(2E)-2-(3,5-Diphenylcyclohex-2-En-1-
Ylidene)Hydrazine]Acetohydrazide (19)
A mixture of compound 18 (3.48 g, 0.01 mol), hydrazine hydrate (0.31 ml, 0.01 mol) in
ethanol (20 ml), was refluxed for 5 hrs. and allowed to cool. The solid product was
collected and crystallized from ethanol as yellow crystal.
Synthesis Of 1-(3,5-Dimethyl-1H-2,3-Dihydropyrazole-1-Yl)-2-[(2E)-(3,5-Diphenyl-
Cyclohexa – 1-En ) Hydrazinyl )Ethanone (20)
A mixture of compound 19 (3.33 g, 0.01 mol), acetyl acetone (0.31 ml, 0.01 mol) and a
catalytic amount of triethyl amine in ethanol (20 ml), was refluxed for 7 hrs. After
cooling the solid product was collected and crystallized from ethanol as deep green
powder.
ANTIMICROBIAL EVALUATION
The newly synthesized heterocyclic compounds 5, 6, 7, 8, 13, 15-18 and 20 were tested
for their inhibitory effect in vitro growth of broad spectrum of bacteria representing one
14

Gram positive bacteria, namely; Bacillus cereus and two Gram negative bacteria, namely;
Pseudomonasaeruginosa and Escherichia coli. These compounds exhibited highly
antibacterial activity against the tested gram positive, but possess potent activity against
gram negative comparable to chloramphenicol as a standard compound. The results of
antibacterial activity are shown in (able 3). The compounds were dissolved in DMSO in
order to ensure that the solvent had no effect on bacterial growth or enzymatic activity,
negative control tests were performed using DMSO. The inhibitory effect of compounds
5, 6 ,7, 8 , 13, 15-18 and 20 in vitro growth of broad spectrum of bacteria representing
one Gram positive bacteria, (Bacillus cereus) and the two Gram negative bacteria,
(Pseudomonasaeruginosa and Escherichia coli) were evaluated using agar diffusion
method (cup and plate method)25 by measuring the zone of inhibition on agar plates at
three different concentrations 10000 ppm, 30000 ppm and 50000 ppm. All plates were
incubated at 37±0.5oC for 24 hrs. The zone of inhibition of the compounds was measured
using cm scale. The results in ( Table 3 ) revealed that the most compounds with good
inhibitory effect at low concentrations ( 10000 and 30000 ppm) and with high effect at
high concentration (50000 ppm) against Gram positive bacteria (Bacillus cereus), except
compounds 7 and 16 revealed the higher effect at (30000 ppm) and the lowest effect at
(10000 and 50000 ppm).
The ionizable forms (A) and (B) are the active forms resulting from the ionization
reactions of compounds 7 and 16 , respectively (Scheme 6) , These ionizable forms were
stabilized by the presence of the conjugation between N- with the double bonds and the
free electrons of different hetero atoms of the compounds 7 and 16. Their interaction
15

with different types of bacteria having the maximum effect at 30000 ppm compared with
that of at 50000 ppm. This may be explained on the basis that the concentration of H+
increase results in the reversible reaction and decreases the concentration of the ionizable
form (Scheme 6), which in turn, decreases the effect of compounds 7 and 16 against
Gram positive bacteria. The weak effect of these compounds against Gram positive
bacteria at 10000 ppm is an expected result because of the lower concentration of the
ionizable form.
At the three different concentrations 10000 ppm, 30000 ppm and 50000 ppm only
compound 5 showed a good effect against Gram negative bacteria namely (Escherichia
coli and Pseudomonasaeruginosa), whereas compounds 8, 17 exhibited a good
inhabitation zone against Gram negative bacteria only (Escherichia coli). The reset of the
tested compounds ( 6 ,7, 13, 15,16,18 and 20 ) have no effect against Gram negative
bacteria.
CONCLUSIONS
2-Chloro-4,6-diphenylcyclohex-1,3-diene-1-carbaldehyde (6) and 3,5-diphenylcyclohex-
2-en -1- hydrazone (11) were used as the starting materials for the synthesis of pyrazol,
thiophene, thiazepine, diazepine and thiazelidene derivatives containing 3,5-diphenyl-
cyclohex-2-en moiety. The antibacterial activities for some of these derivatives were
screened.
16

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17

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18

Table 1 Energy of formation Formation
19

Table 2 Calculated Electronic Parameters
20

Table 3 Antibacterial screening of compounds 5-8, 13, 15-18 and 20
Type of Bacillus Cereus
Pseudomonas
Aeruginosa
Escherichia Coli
Bacteria
Concentrations in ppm
10000 30000 50000 10000 30000 50000 10000 30000 50000
1.3
1
1.4
1.2
1.8
1.5
1.3
1.4
1.8
1.5
1.5
1.5
1.8
1.5
1
1.0
-
1.0
-
1.0
-
1.0
1.1
1.2
5
-
-
-
6
1.2
1.3
1.3
1.1
1.2
1.5
1.1
1.1
-
-
-
-
-
-
7
1.5
1.5
1.7
1.2
1.8
1.7
1.7
-
-
-
0.9
0.9
1.0
8
-
-
-
-
-
-
13
15
16
17
18
20
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
1.1
1.2
1.2
-
-
-
-
-
-
-
-
-
-
-
-
21

Scheme 1
22

Scheme 2
23

Scheme 3
24

Scheme 4
25

Scheme 5
26

Scheme 6
27