Impact of geometric parameters, charge, and lipophilicity on bioactivity of armed quinoxaline, benzothiaole, and benzothiazine: Pom analyses of antibacterial and antifungal activity

Article abstract of DOI:10.1080/10426507.2013.855763

(Equation present) A series of four different armed heterocyclic candidates; 1-(2-methyl-2,3-dihydro-1,3-benzothiazol-2-yl)acetone (2), 1-(3-methyl-4H-1,4-benzothiazin-2-yl)ethanone (3), 2-[(2-aminophenyl)dithio] aniline (4), and 3-hydroxy-3-methyl-4-(3-methyl-2-quinoxalinyl)-2-butanone (5) have been prepared and their microbial activities were evaluated. A correlation of the structure and activities relationships of these compounds with respect to molecular modeling, Lipinski Rule of Five, drug likeness, toxicity profiles, and other physico-chemical properties of drugs are described and verified experimentally. 2014 Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2013.855763

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Impact of Geometric Parameters,
Charge, and Lipophilicity on Bioactivity
of Armed Quinoxaline, Benzothiaole,
and Benzothiazine: Pom Analyses of
Antibacterial and Antifungal Activity
Taibi Ben Haddaa, Fatim Z. Khardlia, Mostafa Mimounia, Maria
Daoudib, Abdelali Kerbalb, Héctor Salgado-Zamorac, Nilesh
Gandhared, Ali Parveze & Siham Lahsasnif
a Laboratoire de Chimie des Matériaux, Faculté des Sciences, UMP
60000, Oujda, Morocco
b Laboratoire Chimie Organique, Faculté des Sciences Dhar Mehraz,
30000, Fès, Morocco
c Departamento de Química Orgánica, Escuela Nacional de Ciencias
Biológicas, Instituto Politécnico Nacional, Col. Santo Tomás, 11340,
México, D. F.
d Department of Chemistry, Nabira Mahavidyalaya, Katol, 661302,
(Maharashtra), India
e Prince Sultan Military Medical City, Riyadh, KSA, 11159
f Department of Chemistry, College of Sciences, King Saud
University, Riyadh, Saudi Arabia
Accepted author version posted online: 17 Mar 2014.Published
online: 12 Jun 2014.
To cite this article: Taibi Ben Hadda, Fatim Z. Khardli, Mostafa Mimouni, Maria Daoudi, Abdelali
Kerbal, Héctor Salgado-Zamora, Nilesh Gandhare, Ali Parvez & Siham Lahsasni (2014) Impact of
Geometric Parameters, Charge, and Lipophilicity on Bioactivity of Armed Quinoxaline, Benzothiaole,
and Benzothiazine: Pom Analyses of Antibacterial and Antifungal Activity, Phosphorus, Sulfur, and
Silicon and the Related Elements, 189:6, 753-761, DOI: 10.1080/10426507.2013.855763
To link to this article: http://dx.doi.org/10.1080/10426507.2013.855763
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Phosphorus, Sulfur, and Silicon, 189:753–761, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.855763
IMPACT OF GEOMETRIC PARAMETERS, CHARGE,
AND LIPOPHILICITY ON BIOACTIVITY OF ARMED
QUINOXALINE, BENZOTHIAOLE, AND BENZOTHIAZINE:
POM ANALYSES OF ANTIBACTERIAL AND ANTIFUNGAL
ACTIVITY
Taibi Ben Hadda,1 Fatim Z. Khardli,1 Mostafa Mimouni,1
Maria Daoudi,2 Abdelali Kerbal,2 He´ctor Salgado-Zamora,3
Nilesh Gandhare,4 Ali Parvez,5 and Siham Lahsasni6
1Laboratoire de Chimie des Mate´riaux, Faculte´ des Sciences, UMP 60000, Oujda,
Morocco
2Laboratoire Chimie Organique, Faculte´ des Sciences Dhar Mehraz 30000, Fe`s,
Morocco
3Departamento de Qu´ımica Orga´nica, Escuela Nacional de Ciencias Biolo´gicas,
Instituto Polite´cnico Nacional, Col. Santo Toma´s 11340, Me´xico, D. F.
4Department of Chemistry, Nabira Mahavidyalaya, Katol 661302, (Maharashtra),
India
5Prince Sultan Military Medical City, Riyadh, KSA 11159
6Department of Chemistry, College of Sciences, King Saud University, Riyadh,
Saudi Arabia
GRAPHICAL ABSTRACT
CH3
O
CH
H
O
CH3
CH3
N
O
S
3
H
O
H
S
S
CH
3
S
CH3
N
N
H
H
N
N
N
H
H
2
3
4
5
Abstract A series of four different armed heterocyclic candidates; 1-(2-methyl-2,3-dihydro-
1,3-benzothiazol-2-yl)acetone (2), 1-(3-methyl-4H-1,4-benzothiazin-2-yl)ethanone (3),
2-[(2-aminophenyl)dithio]aniline (4), and 3-hydroxy-3-methyl-4-(3-methyl-2-quinoxalinyl)-2-
butanone (5) have been prepared and their microbial activities were evaluated. A correlation
of the structure and activities relationships of these compounds with respect to molecular
modeling, Lipinski Rule of Five, drug likeness, toxicity profiles, and other physico-chemical
properties of drugs are described and verified experimentally.
Received 28 February 2013; accepted 11 October 2013.
Address correspondence to Ali Parvez, M.Sc, Prince Sultan Military Medical City, Health Studies Centre,
Riyadh 11159, Saudi Arabia. E-mail: parvezali 81@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
753

754
T. B. HADDA ET AL.
Keywords Antibacterial; antifungal; 1, 3-benzothiazole; 1,4-benzothiazine; quinoxaline: Pe-
tra/Osis/Molinspiration (POM) analyses
INTRODUCTION
Fusarium oxysporum is a highly pleomorphic organism whose many and varied forms
can behave both as saprophytes or parasites in various plants and, among the latter, different
degrees of virulence can arise.1 The number of pathogenic forms is estimated at around 80.
Some of them can infect plants belonging to more than one family, for example, celery and
peas. F. oxysporum f.sp albedinis is responsible for the vascular fusariose of the date palm.
It is a pest that ranks with F. oxysporum f.sp cubense (causal agent of the fusariose of the
banana tree) which is high on the list of serious agricultural problems. Substituted 1, 4-
benzothiazines have recently attracted interest due to their wide spectrum of pharmaceutical
properties,1–6 especially in the field of Ca2+ antagonist activity,7,8 antidiabetic agents,9 or
considerable central nervous system anti-inflammatory activity.10,11 On the other hand, in
recent years, functionalized quinoxalines have been prepared and studied because of their
interesting biological activities and DNA interactive behavior. Some act as antidiabetic
agents and anti-HIV agents. There are some disulfide derivatives such as diallylsulfide
and ajoene which are found in garlic that are well known for their antimicrobial activity
including Gram-positive, Gram-negative, and antifungal properties. They have antiviral
effect also. An increase in the number of sulfur atoms in the sulfide molecules increases
their antifungal activity (with 3 or 4 sulfur atoms).12
For all these reasons, we have focused our attention on functionalized heterocycles
containing quinoxaline, benzothiazole, and benzothiazine systems to investigate their an-
tibacterial and antifungal activity. In this communication, we have reported a new approach
for the synthesis of functionalized heterocycles containing quinoxaline, benzothiazole, and
benzothiazine systems and described the correlation of structure and activities relationships
of these compounds with respect to molecular modeling, Lipinski Rule of Five, drug like-
ness, toxicity profiles, and other physico-chemical properties of drugs with experimental
verification.
RESULTS AND DISCUSSION
Synthesis of Compounds 2–5
Functional benzothiazines were usually obtained via initial cyclo-condensation of
a 2-aminothiophenol with diethylfumarates,13 or via the initial addition of acetylene-
dicarboxylates.14 We have now reported that in the course of our attempts to produce
functionalized benzothiazine of type 3 via the condensation of 2-aminothiophenol 1
with penta-2,4-dione (PDO), a new intermediate type of 1,3-benzothiazol derivative of
type 2 was selectively formed and then used in a clean way to obtain compound 3
(Scheme 1).
The 1-(3-methyl-4H-1,4-benzothiazin-2-yl)ethanone 3 was first prepared by
direct condensation of 2-aminothiophenol 1 with penta-2,4-dione in ethanol at room
temperature with stirring for 24 h and obtained a red product 3 (36% yield) with
contemned by product compound 4 (12% yield). The compound 2 was obtained in traces
(5% yield).

IMPACT OF GEOMETRIC PARAMETERS, CHARGE AND LIPOPHILICITY
755
O
O
N
N
H
5
O
O
CH
3
3
CH3
H3C
O
CH
O
S
CH3
CH3
H
C
CH
H
3
3
S
H
C
CH
3
3
O
O
N
H
O
O
N
H
N
H
X
2
1a-b
3
(a) :X = NH2, (b): X = SH
∇
EtOH/
H
H
N
S
S
N
H
H
4
Scheme 1
To optimize this synthesis, 1 was reacted with a stochiometric equivalent of penta-
2,4-dione (PDO). It results from 2-[(2-aminophenyl)dithio]aniline 4 of type 1 on treat-
ment of 4 with the PDO via a Michael addition of one S-S sulfur atom on the C C of
enol/ketone PDO tautomer, followed by a second Michael addition of the NH2 nitrogen
on a resulting in-situ α,β-unsaturated ketone. This reaction contrasts with usual 1 and
PDO intermolecular condensation in this class of compounds as N-alkylation occurs in
the formation of 1,4-bezothiazines, obtained as a principal product in the synthesis of the
analogous molecule of type 1,4-benzothiazine.15 The initial synthesis of 1, 4-benzothiazine
derivatives was reported using 2-aminothiophenol, which was condensed with activated
acetylenic esters.14,16,17
The 2-[(2-aminophenyl)dithio]aniline (4) generated from a dimerization reaction of
2-amino-thiophenol 1 by simple stirring in ethanol is a good way to control a selective
formation of (4E)-4-[(2-mercaptophenyl)imino]pentan-2-one (2) at low temperature. The
transformation reaction of 2 to 3 is competed by a thermal reaction of 2 in solution
of ethanol. Thus, we found that the preparation of 1,4-benzothiazolin derivatives can be
successfully carried out as a one-pot clean process starting with thermally unstable 1,3-
benzothiazol derivatives in boiling organic solvent such as ethanol. All the reactions were
monitored by using thin layer chromatography technique.

756
T. B. HADDA ET AL.
Table 1 Osiris calculations of compounds 2–5
Toxicity risck[a]
Drug-score calculations[b]
Compound
MW
MUT
TUMO
IRRI
REP
CLP
S
D-L
D-S
2
3
207
250
3.23
3.75
−4.02
−3.97
2.03
0.74
0.12
−6.2
4
5
302
244
2.77
1.59
−3.72
−2.22
−3.29
2.95
0.09
0.91
[a]MUT: mutagenic; TUMO: tumorigenic; IRRI: irritant; REP: reproductive effective.
[b]CLP: cLogP, S: Solubility, DL: Druglikness, DS: Drug-Score.
X-ray Diffraction Study of Compounds 2–5
Indeed this survey, first on the crystal of compound 2, permitted us to confirm that the
two Ha and Hb hydrogen atoms carried by the C9 carbon atom adopt a geminal-disposition
(Figure 1).
The direct synthesis of 1,4-benzothiazin-2-yl)ethanone 3 from 2 is not only an original
method that interests organic chemists but it is also a potential way to get colored products
Figure 1 Crystallographic structure of armed compounds 2–5.19–23

IMPACT OF GEOMETRIC PARAMETERS, CHARGE AND LIPOPHILICITY
757
under photo or thermal initiations. Potentially many applications in food quality control
and visible or laser-ink interaction for printing applications could be developed.
To our knowledge, this is the first new opening/closing five-membered 1,3-
benzothiazole ring leading to a six-membered 1,4-benzothiazine ring. Control, opti-
mization, and selective synthesis of focused compounds (2 or 3 but not their mixture)
looks to be an interesting and clean direction for further development of new bioactive
1,3-benzothiazol-2-yl)acetone and 1,4-benzothiazin-2-yl)ethanone derivatives considered
until this time as potential pharmaceutical agents.18
BIOLOGICAL EVALUATION
Evaluation of Antibacterial Activity of Compounds 2–5
Compounds 2–5 were tested for their antibacterial activities against Proteus vulgaris
(PVR), Pseudomonas aeruginosae (PSA), Esherchia coli (Ecoli), and Staphylococcus au-
reus (STA) using the paper disk method. All stock cultures were grown on tryptic soy
agar plates. Test strains were transferred to fresh tryptic soy broth before use and a disk
containing only DMSO was used as negative control. The compounds were found to be
inactive at concentrations of up to 56 μg/disk, except for disulfide (4), which showed
moderate antibacterial activity, affording inhibitory zone sizes of 11 mm against PRV at a
concentration of 2 μg/disk (Table S1 Supplemental Materials).
Evaluation of Antifungal Activity of Compounds 2–5
Antifungal activity was assessed against the albedinis strain. The functionalized
heterocyclic compounds were dissolved in dimethylsulfoxide with 50% ethanol and then
added at different concentrations into the solid culture media. The percentage inhibition of
growth was expressed in terms of the ratio of diameter of the treated mycelium to that of
the untreated control. The most effective inhibitor is 4, which produces 66% inhibition of
the growth of Fusarium in the presence of 50 mg/L. Molecules 2, 3, and 5 are less effective
but 3 produces appreciable growth inhibition at comparable concentration (44% inhib).
Compounds 2 and 5 only inhibit growth weakly and are considered essentially inactive
(Table S1 Supplemental Materials).
POM VIRTUAL SCREENING
Molecular Properties Prediction
Molecular properties, mainly hydrophobicity, molecular size, flexibility, and the pres-
ence of various pharmacophoric features influence the behavior of molecules in the living
organism, including bioavailability. Thus, in order to achieve good oral drugs, we have
subjected the armed compounds 2–5 for the prediction of lipophilicity, solubility, and Lip-
inski “Rule of Five” 24 and other properties for filtering the compounds for antimicrobial
screening.
For good membrane permeability, logP value should be inferior to 5.24 All the title
compounds 2–5 have clogP value in the range of 1.59–3.75 (Table 1), but this doesn’t
guaranty any antimicrobial activity. So, we should take into consideration other more
important factors (chemical and geometrical structure of pharmacophore site as we have
previously defined it via our new POM theory).25–30 For this reason, we have created POM

758
T. B. HADDA ET AL.
Table 2 Molinspiration calculations of compounds 2–5
Molecular properties[a]
Compound TPSA NONI NV nrotb VOL GPCRL
Drug-likeness[b]
KI NRL
ICM
PI
EI
2
3
4
5
29
33
52
63
1
1
4
1
0
0
0
0
2
1
3
3
189
183
214
230
−1.21
−0.74
−0.10
−0.10
−0.66 −1.70 −1.37 −1.01
−0.41 −0.95 −0.76 −1.10
−0.15 −0.14 −0.62 −0.45
−0.07 −0.68 −0.10 −0.26
−0.61
−0.54
0.13
−0.11
[a]TPSA: Total Polar Surface Area; VOL: Volume; ONI: OH-NH Interraction; NV: Number of Violation of
Lipinski rules.
[b]GPCRL: GPCR ligand; ICM: Ion Channel Modulator; KI: Kinase Inhibitor; NRL: Nuclear Receptor Ligand.
(Petra/Osiris/Molinspiration) theory which involves three complementary softwares. The
Toxicity risks were calculated from Osiris Bioinformatics and they are given in Table 1.
Two of four compounds are less toxic (2 and 5).
The compounds in this series 2–5 in general possess limited number of rotatable
bonds (1–3) and in consequence, exhibit low conformational flexibility (Table 2). Molecular
polar surface area (TPSA) is a very useful parameter for the prediction of drug transport
properties. TPSA is a sum of surfaces of polar atoms (usually oxygen, nitrogen and attached
hydrogen) in a molecule.
The Lipinski “Rule of Five” states that the molecules 2–5 with good membrane
permeability have clogP < 5, molecular weight <500, number of hydrogen bond acceptors
<10, and number of hydrogen bond donors <5.24 This rule is widely used as a filter for
drug-like properties. All the title compounds 2–5 followed the Lipinski “Rule of Five” but
this information is limited to bioavailability and can’t lead us to the nature of bioactivity
(Antibacterial, Antiviral of Antifungal type). So, the Drug-Score (Table 1) and the Drug-
likeness (Table 2) parameters were calculated respectively from Molinspiration and Osiris.
The pi-charge of each heteroatom is calculated from Petra (Table 3).
EXPERIMENTAL
1-(2-methyl-2,3-dihydro-1,3-benzothiazol-2-yl)acetone 2 used in this work was pre-
pared from 2-aminobenzothiol 1 and pentan-2,4-dione by a procedure described previ-
ously.31 Melting points were determined with a Buˆchi-535 capillary melting point apparatus
and are uncorrected. 1H and 13C NMR spectra were recorded in CDCl3 on Bruker AC 200
(operating at 300 MHz). spectrometer; chemical shifts are reported in δ (ppm) relative to
Table 3 Pi-charge calculations of compounds 2–5
Pi-charge of heteroatoms
Pharmacophore
Compound
N-1
N-2
S-1
S-2
O-1
O-2
(X—Y)
2
3
4
5
0.14
0.15
0.15
0.06
—-
—-
0.15
0.06
0.00
−0.05
−0.02
—-
—-
—-
−0.33
−0.05
—-
—-
—-
—-
−0.1
(O—S)
(O—S)
(NH—-S)
(OH—N)
−0.02
—-
0.00

IMPACT OF GEOMETRIC PARAMETERS, CHARGE AND LIPOPHILICITY
759
Me4Si. Infra-red spectra of compounds were recorded in KBr pellets using a Beckman 310
spectrometer. Mass spectra of compounds were measured with Hewlett packard 5989-A
Mass spectrometer (70 eV) and elemental analysis at Universite´ Paul Sabatier, Toulouse;
France.
Synthesis of Compounds (2–5)
1. Use of 2-aminothiophenol and Penta-2,4-dione. The regeneration and
purification of 1, 3-benzothiazol 2 has already been reported in the literature. Our new
optimization and synthetic methodology of 2, which has been adapted from literature, is
described below.
The preparation of a mixture of 2, 3, and 4 is described as the general procedure:
2-aminothiophenol (5 mL, 40 mmol) 1, penta-2,4-dione PDO (2 mL, 20 mmol), and of
EtOH (20 mL) at room temperature afforded a complex mixture of compound 2 (traces),
derivative 3 (3 g, 36%) and the dimer 4 (1 g, 12%).
2. Use of Compound 4 and Penta-2,4-dione. To of 2-[(2-aminophenyl)dithio]
aniline (1.0 g 4.03 mmol) 4, were added penta-2,4-dione (0.48 mL, 4.03 mmol) and EtOH
(10 mL) and the mixture was magnetically stirred at room temperature for 16 h. After re-
moval of 2-[(2-aminophenyl)disulfanyl]phenylamine, the solution was kept at atmospheric
pressure at room temperature to give red-orange crystals of compound 3 (0.75 g, 91%).
3. Use of 1-(2-methyl-2,3-dihydro-1,3-benzothiazol-2-yl)acetone (2).
Production of pure 1,4-benzothiazine 3: The 1,3-benzothiazol 2 which is slightly colored
in the time to red-orange was dissolved in 15 mL of ethanol, the temperature of the reaction
mixture was increased to 60–70◦C, and the mixture was magnetically stirred for 2 h. The
pure 3 was easily obtained by eliminating the solvent (90% yield of pure (3).
4. Preparation
of
3-hydroxy-3-methyl-4-(3-methylquinoxalinyl)-2-
butanone (5). The o-phenylenediamine 1a (10.8 g, 100 mmol) and 2,3-butadione 2
(8.8 g, 100 mmol) were stirred in refluxing ethanol (100 mL) for 4 h. After cooling the
mixture to room temperature, the volume of solvent was reduced at on a rota-evaporator
and the desired compound 5 was separated as byproduct from 2,3-dimethyl-quinoxaline as
analytically pure yellow crystals by using chromatography on silica and hexane as eluent
(1.2 g, 25%).
Spectral characterization data of compounds 2–5 is given in supplementary material
file.
BIOLOGICAL EVALUATION
The antifungal activity of the compounds was measured against Fusarium oxysporum
f.sp. albedinis. A stock culture of Fusarium was isolated from a date palm infected by the
vascular fusariose. The organism was grown aerobically in liquid Czapek medium of the
following composition: 2 g/L of NaNO3, 1 g/L of K2HPO4, 0.5 g/L of MgSO4·7H2O),
0.01 g/L of FeSO4·7H2O, and 30 g saccharose/L. The pH was adjusted to 5.4 with citric
acid. All liquid cultures were inoculated into 100 mL Erlenmeyer flasks with a narrow
collar containing 20 mL of medium at 25◦C, in a water bath, with horizontal rotary agi-
tation at 70 rpm. The growth was followed by measuring the optical density with a Cecil
spectrophotometer at a wavelength of 620 nm and by counting the organisms on a cell
of Molasses under an optical microscope. Cultures on solid medium were seeded in Petri
dishes 50 mm in diameter at 28◦C in a thermostatically controlled drying oven. The growth

760
T. B. HADDA ET AL.
was followed by counting colonies for yeast and bacteria and by measuring the diameter of
the mycelium for Fusarium.
CONCLUSION
Four functionalized heterocycles including quinoxaline, disulfide, benzothiazole, and
benzothiazine systems, were prepared and optimised from the available commercial com-
pounds (2-amino-phenol and 2-aminothiophenol). Their structures were confirmed on the
basis of 1H and 13C NMR, the crystallographic experiments and comparison with literature
values. The antimicrobial activity of pure crystal compounds 2–5 was tested against four
bacterial strains and one fungicidal organism. Only 2-[(2-aminophenyl)dithio]aniline (4)
showed potential antibacterial and antifungal activity.
FUNDING
The authors would like to extend their sincere appreciation to the Deanship of Sci-
entific at King Saud University for its funding of this research through the Research Group
Project no. RGP-VPP-222.
SUPPLEMENTAL MATERIAL
Supplementary data of this article can be accessed on the publisher’s website,
www.tandfonline.com/gpss
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