Petra, osiris, and molinspiration together as a guide in drug design: Predictions and correlation structure/antibacterial activity relationships of new N-sulfonyl monocyclic β-lactams

Article abstract of DOI:10.1080/10426500902953953

We report in this article the design and calculated molecular properties of 18 new mono-cyclic β-lactams 4-21, on the basis of one hypothetical antibacterial pharmacophore structure designed to interact with both of Gram-positive bacteria and Gram-negative bacteria. The in vitro biological evaluation of these compounds allowed us to point out new potential non-nucleoside hits, with MIC values in the range of 2-8 μg/mL active against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. A correlation structure/antibacterial activities relationship of these monocyclic β-lactams is described. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426500902953953

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Petra, Osiris, and Molinspiration
Together as a Guide in Drug Design:
Predictions and Correlation Structure/
Antibacterial Activity Relationships of
New N-Sulfonyl Monocyclic β-Lactams
A. Jarrahpour a , M. Motamedifar b , M. Zarei a , M. H. Youssoufi c ,
M. Mimouni c , Z. H. Chohan d & T. Ben Hadda c
a Department of Chemistry, College of Sciences , Shiraz University ,
Shiraz, Iran
b Department of Bacteriology and Virology , Shiraz Medical School ,
Shiraz, Iran
c Laboratoire Chimie des Matériaux, Faculté Sciences , Oujda,
Morocco
d Department of Chemistry , Bahauddin Zakariya University , Multan,
Pakistan
Published online: 03 Feb 2010.
To cite this article: A. Jarrahpour , M. Motamedifar , M. Zarei , M. H. Youssoufi , M. Mimouni ,
Z. H. Chohan & T. Ben Hadda (2010) Petra, Osiris, and Molinspiration Together as a Guide in Drug
Design: Predictions and Correlation Structure/Antibacterial Activity Relationships of New N-Sulfonyl
Monocyclic β-Lactams, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:2, 491-497
To link to this article: http://dx.doi.org/10.1080/10426500902953953
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Phosphorus, Sulfur, and Silicon, 185:491–497, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902953953
PETRA, OSIRIS, AND MOLINSPIRATION TOGETHER AS A
GUIDE IN DRUG DESIGN: PREDICTIONS AND
CORRELATION STRUCTURE/ANTIBACTERIAL ACTIVITY
RELATIONSHIPS OF NEW N-SULFONYL MONOCYCLIC
β-LACTAMS
A. Jarrahpour,1 M. Motamedifar,2 M. Zarei,1 M. H. Youssoufi,3
M. Mimouni,3 Z. H. Chohan,4 and T. Ben Hadda3
1Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran
2Department of Bacteriology and Virology, Shiraz Medical School, Shiraz, Iran
3Laboratoire Chimie des Mate´riaux, Faculte´ Sciences, Oujda, Morocco
4Department of Chemistry, Bahauddin Zakariya University, Multan, Pakistan
We report in this article the design and calculated molecular properties of 18 new mono-cyclic
β-lactams 4–21, on the basis of one hypothetical antibacterial pharmacophore structure
designed to interact with both of Gram-positive bacteria and Gram-negative bacteria. The
in vitro biological evaluation of these compounds allowed us to point out new potential non-
nucleoside hits, with MIC values in the range of 2–8 µg/mL active against Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. A correlation
structure/antibacterial activities relationship of these monocyclic β-lactams is described.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Antibacterial activity; drug design; N-sulfonyl β-lactams; virtual screening
INTRODUCTION
The β-lactam system has been shown to be an efficient precursor for many synthetic
industrial antibiotics including penicillin derivatives.1 Although antibiotic-containing rings
fused to the β-lactam ring display interesting biological properties, they become less effi-
cient because of emergence of new MDR-bacterial and viral strains. So the pharmaceutical
industry turned to other derivatives that are versatile intermediates for the synthesis of
important products such as penams, cephems, clavulanates, monobactams, carbapenems,
and trinems.2,3 Monocyclic β-lactams have also attracted much attention owing to their
Received 24 January 2009; accepted 5 April 2009.
The authors thank the Shiraz University Research Council for financial support (Grant No. 87-GR-SC-23).
We would like to thank the ACTELION, the Biopharmaceutical Company of Switzerland, for the online molecular
properties calculations.
Address correspondence to A. Jarrahpour, Department of Chemistry, College of Sciences, Shiraz University,
Shiraz 71454, Iran. E-mail: aliasghar6683@yahoo.com and T. Ben Hadda, Laboratoire Chimie des Mate´riaux,
Faculte´ Sciences, 60000 Oujda, Morocco. E-mail: tbenhadda@yahoo.fr
491

492
A. JARRAHPOUR ET AL.
important pharmacological properties.4 Some monocyclic β-lactams containing the ph-
thalimido group have shown good antibacterial activity.5,6 Recently scientists have found
that monocyclic β-lactams are also inhibitors of cytomegalovirus protease,7,8 inhibitors
of thrombin and tryptase,9,10 cholesterol absorption inhibitors,11,12 human leukocyte elas-
tase (HLE) inhibitors,13,14 porcine pancreatic elastase (PPE) inhibitors,15 cysteine protase
inhibitors,16,17 and anticancer agents.18,19 In addition to their diverse current uses as pharma-
ceuticals, β-lactams are of interest as synthetic building blocks20,21 and in the semi synthesis
of Taxol.22 Selective bond cleavage of the strained β-lactam ring coupled with further in-
teresting synthetic transformations renders these fascinating molecules powerful synthetic
building blocks.23,24 In addition, the existence of the methoxy group on the molecules en-
hances the various biological activities.25 The high synthetic utility and pharmacological
importance of the β-lactam family have prompted us to realize a pharmacological study of
the antibacterial activity of the compounds 4–21 (Scheme 1).
O
O
O
O
N
R2
R1
R1R2CHCOCl
CH2Cl2/ Et3N
N
O
1
4-6
O
O
CAN
CH3CN
H2O
O
O
O
O
R2
R2
R1
R3SO2Cl/ CH2Cl2
Et3N/ DMAP
R1
O
N
NH
7-9
S
O
R3
O
O
10-21
NO2
O
R1 =3-NO2PhthN, PhO
R2 = H, Me
N
3-NO2PhthN :
R3 = Me, Ph, 4-MePh, 2-naphtalene
O
Scheme 1 General synthesis of monocyclic β-lactams 4–21.
Previously, antibacterial screening showed that compounds bearing a formyl, hy-
droxy, or nitroso side chain in position 3 are highly active against Mycobacterium tu-
berculosis.26,27 From general structure–activity relationship observations, it appears that
functionalized side chain(s) such as [X-(C)n-Y], where (X,Y = O,N) and (n = 2,3), are
crucial for bioactivity. These atoms or centers that have critical interactions with the bac-
terial cell receptor constitute the pharmacophore and are vital for antimicrobial activities.
These interactions must have typically precise geometric requirements that are readily de-
scribed in terms of the distances between the terminal atoms and their orientation in the
pharmacophore sites.28b

PETRA, OSIRIS, AND MOLINSPIRATION TOGETHER
493
Figure 1 Possible interactions between antibacterial or anti-HIV-1 drugs and their specific biological targets.
As an extensive continuation of our study on the structure–antibacterial activity re-
lationships in β-lactam derivatives, we performed an investigation of compounds 4–21,
because they represent an attractive model for a theoretical and experimental study of the
pharmacophore, and their medical applications because of the large variability and combi-
nation in their substituents (R1, R2, and R3). Moreover, given the current interest in selective
drugs through the development of molecules that recognize simultaneously specific bacte-
rial and HIV-1 sites, we became interested in the combined synthesis and antibacterial and
anti-HIV screenings of heterocycles having two or more flexible pharmacophore systems
(O C C O and O C O N) as is postulated in Figure 1.
The main interesting tasks of this work are as follows: (i) Develop robust predic-
tion models for the heterocycles/bacteria inhibitory properties (solubility, MT inhibition,
stability, selectivity, etc.) of small molecules with the estimation of confidence of these
models; (ii) interpret the calculated/predicted results for the design of new compounds;
(iii) perform docking or pharmacophore modeling based on crystal structures to support
the lead optimization process; (iv) combine the antibacterial pharmacophore site with a
selective anti-HIV pharmacophore site without altering activity of the first one; (v) find the
right molecule for the right target.
RESULTS AND DISCUSSION
Chemistry
Monocyclic β-lactams 4–6 (Scheme 1) were obtained by the [2+2] cycloaddition of
imine 1 with ketenes derived from acyl chlorides 2, 3, and phenoxyacetyl chloride in the
presence of triethylamine in dry dichloromethane at –10 ◦C, as it was previously reported
recently.29 Compounds 4–21 are stable at ambient temperature. Their structures have been
determined by IR, MS, and NMR (1H and 13C) spectroscopy.29
Antibacterial Activity and Preliminary Observations
The antibacterial activity of compounds 4–21 is represented in Table I (available in
the Supplemental Materials online).
PETRA Calculations
PETRA is a program package comprising various empirical methods for the calcu-
lation of physicochemical properties in organic molecules. All methods are empirical in
nature and have been developed over the last 20 years in the research group of Gasteiger.30

494
A. JARRAHPOUR ET AL.
The following chemical effects can be quantified: heats of formation, bond dissociation en-
ergies, sigma charge distribution, π-charge distribution, inductive effect, resonance effect,
delocalization energies, and polarizability effect.30
In order to check the apparent antibacterial activity of compound 19 and to look for
evidence of structure–activity via Gram-positive and Gram-negative bacteria, we performed
Petra calculations30 with 4–21 (Table II, available in the Supplemental Materials online).
The PETRA software calculations confirmed that all compounds 4–21 have a clear
preference for forming antibacterial dipolar pharmacophore sites though their estimated
partial π charges respectively for two oxygen atoms are of different charges (–0.1784 e
and +0.0435 e) for compound 17 for example. The PETRA calculations with the other
β-lactam derivatives 4–21 are shown and are summarized in Table II.
Compound 21 has the same partial π-charges [–0.1779 e for O of SO2 and +0.0436
e for O of methoxy almost as tightly as 17, but its activity, as evidenced by a lack of
observable antibacterial results, is considerably better (2–8 for 21 instead of 8–128 µg/mL
for 17). In the light of these observations, the lack of antibacterial activity by the latter three
compounds (10, 17, and 21) is explicable in terms of the existence of dipolar pharmacophore
site (O---O).
The increase in activity could be due to the increase of the hydrophobic character
that the alkyl and alkyloxy groups confer on the molecule. Hydrophobic molecules with
rigid, planar structures such as aromatic rings, have been shown to have the ability to insert
into membranes and induce localized permeability changes leading to leakage out of the
membrane.31 The combination of methoxy, sulfonyl, and Pho groups (18–21), while also
hydrophobic and very easily inserted into the membrane, are much less likely to cause
disruption of the lipid packing order. That can be explained by possible cell membrane
facility, as the 2-naphtalene group is too lipophylic to have this type of effect. The enhanced
antibacterial inhibition observed in the presence of 17, 18, 19, and 21 is then more likely
due to its interaction with some intracellular target. The presence of a strong or poor
electron-withdrawing group must alter the nature of the compound in such a way as to
promote binding to the target(s) (Scheme 2).
3
O
3
O
3
O
2
O
R2
R1
δ+
2
2
R2
O
R1
O
δ+
R2
N
O
1
O
5
R1
N
S
O
δ-
1
δ-
4
O
N
1
O
R3
δ-
δ+
H
4
O
4-6
7-9
Scheme 2
10-21
Osiris Calculations
The Osiris Property Explorer used in this article is an integral part of Actelion‘s
in-house substance registration system.32 It allows a user to draw chemical structures

PETRA, OSIRIS, AND MOLINSPIRATION TOGETHER
495
and calculates on-the-fly various drug-relevant properties whenever a structure is valid.
Prediction results of compounds 4–21 molecular properties (solubility, druglikeness, and
drug-score) are abstracted (Table III, available online in the Supplemental Materials).
Molinspiration Calculations
cLogP (octanol/water partition coefficient) is calculated by the methodology devel-
oped by Molinspiration as a sum of fragment-based contributions and correction factors. The
method is very robust and is able to process practically all organic and most organometallic
molecules. Molecular polar surface area (PSA) is calculated based on the methodology
published by Ertl et al.33 as a sum of fragment contributions. O- and N-centered polar
fragments are considered. PSA has been shown to be a very good descriptor characterizing
drug absorption, including intestinal absorption, bioavailability, Caco-2 permeability, and
blood-brain barrier penetration.33 Prediction results of compounds 4–21 molecular proper-
ties (TPSA, GPCR ligand, and ICM) are valued (see Table IV in the Supplemental Materials
online).
β-Lactam 4 is among the least active substances to have been evaluated as antibac-
terial agents in this series (MIC > 128 µg/mL). Accordingly, an effort was initiated to
establish a pharmacophore hypothesis to delineate the requirements of the active site via
a comprehensive program of analogue synthesis and evaluation of the effects of structural
modification(s) on antibacterial activity of 4.
We then set out to determine the resultant in vitro effects of chemical alterations
in each region. The unsubstituted N atom of β-lactam-ring of 7–9 endowed antibacterial
activity (MIC > 128 µg/mL). The modulating antibacterial effect(s) of substituents having
different electronegative properties, located at the N(1) and C(3) sites comprising the SO2
and 3-NO2PhthN or PhO substituents of C(3), were ascertained next.
A combination of the PhO (R1) and 2-naphthalene (R3) substituents located respec-
tively at the 3,1-positions on the β-lactam ring of 21 generated higher antibacterial activity
relative to 4–20 in both the Gram-positive and Gram-negative inhibition tests. However,
in general a 2,3-dimethoxyphenyl of the position 4 of β-lactam proved to be unhelpful
as a substituent. We postulate that the strong tendency to form a (Oδ+---O δ−) dipolar
pharmacophore site in the predominant (cisoidal) form is likely to be responsible for the
lack of biological activity observed with these semi π-conjugated β-lactam derivatives.
If this hypothesis is correct, by modifying 21, we may be able to modulate the degree of
interaction of the compound with various bacteria.
CONCLUSIONS AND PERSPECTIVES
The functionalized β-lactam compounds 4–21 can easily be prepared.29 These com-
pounds typically could form the highly interesting combined two or more pharmacophore
sites in one molecule. A number of important points emerge concerning their antibacterial
properties. The positive results we have recorded, while encouraging for purposes of new
drug design, confirm that very likely most of these compounds could be used without great
risk of toxicity in diverse antibacterial activity. Based on their structural properties, these
compounds may be useful as antitubercular agents with high activity or as potential antiviral
agents (Scheme 3).34
These results prompt two pertinent observations: (i) This type of β-lactam can furnish
an interesting model for studying the interaction of antibiotics with HIV-integrase target

496
A. JARRAHPOUR ET AL.
O
N
O
O
3
O
N
2
O
O
δ-
δ+
N
O
1
O
5
S
O
δ-
δ-
4
R3
δ-
Scheme 3
because the possible negative center-bonding of a O1 and O of 3-NO2PhthN group to
the positively charged centers of catalytic integrase domain is generally favored; (ii) the
flexible pharmacophore site(s) geometric conformation enables us to prepare molecules for
multi-therapeutic materials (anti-HIV and anti-Mycobacterium tuberculosis).
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