Houshdar Tehrani, M., Zarghi, A., Erfani Jabarian, L. (2010). Design and Synthesis of New Imidazole Derivatives of Captopril. Iranian Journal of Pharmaceutical Research, Volume 4(Number 1), 37-41.
MH Houshdar Tehrani; Afshin Zarghi; L Erfani Jabarian. "Design and Synthesis of New Imidazole Derivatives of Captopril". Iranian Journal of Pharmaceutical Research, Volume 4, Number 1, 2010, 37-41.
Houshdar Tehrani, M., Zarghi, A., Erfani Jabarian, L. (2010). 'Design and Synthesis of New Imidazole Derivatives of Captopril', Iranian Journal of Pharmaceutical Research, Volume 4(Number 1), pp. 37-41.
Houshdar Tehrani, M., Zarghi, A., Erfani Jabarian, L. Design and Synthesis of New Imidazole Derivatives of Captopril. Iranian Journal of Pharmaceutical Research, 2010; Volume 4(Number 1): 37-41.
Design and Synthesis of New Imidazole Derivatives of Captopril
A new series of alkylthio imidazole analogues of captopril, an ACE inhibitor used in the treatment of hypertension, was designed and synthesized in order to obtain agents more active than captopril with less side effects. All the compounds thus prepared were purified and characterized by IR, NMR and Mass analytical instruments.
A new series of alkylthio imidazole analogues of captopril, an ACE inhibitor used in the
treatment of hypertension, was designed and synthesized in order to obtain
agents more active than captopril with less side effects. All the compounds
thus prepared were purified and characterized by IR, NMR and Mass analytical
instruments.
Angiotensin converting Enzyme (ACE) plays an
important role in the control of arterial blood pressure. The enzyme is
responsible for conversion of the decapeptide angiotensin I into the
vasopressor agent, angiotensin II. It is a zinc-containing enzyme that cleaves
dipeptide units from its peptide substrate (1). An important competitive
inhibitor of ACE is captopril, which inhibits conversion of the relatively
inactive angiotensin I to the angiotensin II. According to the mechanism
proposed by Ondetti and colleagues (2), captopril interacts with the enzyme
through several bonds, i.e. electrostatic, hydrogenic and lipophilic
connections (Fig 1). Among these is a coordinance bond formed between the free
thiol group of captopril and zinc ion in the active site of ACE. Captopril,
although is an important orally active ACE inhibitor, produces some side
effects. The two most common side effects, skin rashes and taste disturbances
are attributed to the presence of the sulfhydryl group (3). An alternative
approach to ACE inhibitors developed by Patchett and colleagues is the
preparation of
N-carboxyalkyl dipeptides which with some modification gives enalaprilat, a
compound approximately ten fold more potent than captopril (4). Enalaprilat, a
di-acid in which the SH group of captopril is replaced by a carboxyl moiety,
has however poor oral absorption. But the ethyl ester derivative, enalapril, a
mono acid, is a prodrug form which is orally well absorbed. In fact, the
addition of some lipophilic groups at the ends and in the middle of the
structure can improve oral absorption of ACEI molecules (2,5,6). In the present
study several molecules have been designed and synthesized as imidazole
derivatives of captopril in such a way that cover those factors necessary for
tight binding to ACE with acceptable oral absorption and less side effects
comparing to captopril.
Experimental
For molecular modeling and design a PC Model?
6.0 software implementing MMX force field program was used (7). Synthesis of
the compounds was performed by chemical reagents purchased from Merck company.
The synthesized compounds were visualized by UV light of λ=254
nm. IR spectra were recorded on perkin Elmer model 840. 1HNMR
spectra were recorded on a varian-400 spectrometer and Mass spectrometry was
performed on a finnigan TSQ 70 Mass spectrometer at 70 ev. Elemental analyses
(C, H, N) were realized on a Carlo-Erba EA 1108-elemental analyzer.
Molecular Design
Some new imidazole derivatives of captopril
were designed as shown in Figure 2. The structure of captopril was used as the
starting point. Since proline is the C-terminal part of usual ACEI molecules,
this amino acid structure was preserved in the present molecular design. As the
second part of ACEI molecules, an imidazole ring was constructed to mimic
histidine residue in ACE main substrate, angiotensin I. N-Methyl group on the
imidazole N-1 was proposed to occupy S1 site of the enzyme.
Alkylated thiol on this ring was designed to save connection with zinc ion of
the enzyme as well as to fill S1 site of ACE as an additional
lipophilic site as proposed by Patchett et al (2). By designing the
complete ACEI structures employing PC Model?, the molecules were
energy minimized and then superimposed on captopril structure using MMX force
field analysis (Figure 3).
Chemistry
The designed molecules were synthesized
following the steps outlined in scheme 1. At first
5-hydroxymethyl-1-methyl-2-thio-imidazole I was prepared using dihydroxy
acetone (8,9). Reaction of I with alkyl iodide afforded corresponding
substituted alkylthio imidazole II (10). As the next step, oxidation of the
carbinol group was prerequisite for amide bond formation between the imidazole
moiety and amino acid proline. Oxidation may give carboxylic acid directly from
alcohol or indirectly through aldehyde formation. Considering yield and
availability of reagents, preparation of carboxylic acid via aldehyde was
practiced. For the final step, condensation of proline with the imidazole was
put forward. This condensation may proceed by several routes:
1)?? Direct coupling of proline with
imidazole in alkaline medium (11) or in the presence of DCC in DMF (12),
2)?? Coupling of proline with the imidazole
acyl chloride in THF (12) and dioxane (13),
3)?? Coupling of esterified proline with the
imidazole by using ethyl chloroformate and triethylamine (14).
In practice, coupling in alkaline solution
gave low yield since amide formation was reversible. Condensation reaction by
DCC showed difficulty in working up of the product. Furthermore, coupling by
imidazole acyl chloride did not proceed well. However, esterified proline could
couple well with the imidazole in the presence of ethyl chloroformate.
Hydrolysis of the resultant product gave the desired derivative. The purity of
all compounds was determined by thin-layer chromatography using several solvent
systems of different polarities.
A mixture
of potassium thiocynate (0.7 mol, 69 g), methylamine HCl (0.6 mol, 41.3 g) and
dihydroxyacetone (0.46 mol, 42.6 g) in a solution of acetic acid (54 ml) and
1-butanol (340 ml) was stirred at room temperature for 60 h. Water (70 ml) was
then added to the reaction mixture and the precipitate thus formed was filtered
and washed with water (200 ml), then ether (200 ml) and dried at 50-60?C. The
product I (40 g) was obtained at 58% yield, mp 202-207?C (ref. (8) 203-205 ?C),
To the
stirring solution of compound I (21 mmol, 3 g) and sodium hydroxide (25 mmol, 1
g) in 5 ml of hydromethanol, a solution of alkyl iodide (30 mmol) in methanol
was added dropwise. The reaction mixture was stirred at room temperature for 3
h. Methanol and excess alkyl iodide were removed under reduced pressure. The
residue was saturated with NaCl and then extracted three times (3?20 ml) with
choroform. After solvent evaporation, a yellow precipitate was obtained;
yields? 70-82 %, mps.:(methyl) 182?C, (ethyl) 179?C, (propyl) 175?C. (ref. (9).
182?C (methyl), 180?C (ethyl), 174?C (propyl)), IR(KBr): ν
3300 (OH), 1600 (C=C).?
3) 5-Formyl-1-methyl-2-alkylthio
imidazole (III):
A mixture of compound II (12 mmol, 2.88 g)
with activated manganese dioxide (~120 mmol) in chloroform (50 ml) was refluxed
for 12 h. After cooling, the mixture was filtered on celite and the filtrate
was separated and the solvent was then evaporated.
The aldehydes were thus obtained as fine
yellow powders; yields 93-95%, mps: (methyl) 120?C (ethyl) 118?C (propyl)
116?C. (ref. (9). 122?C (methyl), 120?C (ethyl), 115?C (propyl)), IR(KBr): ν 2800 (C-H aldehyde), 1660-1680 (C=O), 1600 cm-1 (C=C).
Addition of silver nitrate (in water, 26.4
mmol) to sodium hydroxide solution (52.5 mmol) gave silver oxide as an
oxidating reagent. To an ice-cooled reagent mixture, III (12.8 mmol) was
gradually added with stirring. Oxidation was completed after 15 min. The
reduced silver was filtered on celite. The filtrate was pH adjusted (5-5.5) and
then extracted by n-butanol. After solvent evaporation, a yellow powder was
obtained: yields 60-63%; mps: (methyl )155?C, (ethyl )187?C, (propyl) 230?C.
IR(KBr): ν 3300
(OH), 1680 (C=O), 1600 cm-1 (C=C). Elemental microanalyses were
within ? 0.4% of the theoritical values for C, H, N.
5) Ethyl L-prolinate (V)12 :
L-proline
(25 mmol) was suspended in absolute ethanol (20 ml) under dried HCl gas. After
30 min, the excess ethanol was evaporated and an oily residue was obtained;
yield 97%, IR(CHCl3): ν 3400 (NH), 1740 (C=O),
1220 cm-1(C-O).
To a mixture of dried triethylamine (50 mmol,
5.0 g) dissolved in dried chloroform (30 ml), compound IV (25 mmol) was added
under nitrogen. The mixture was cooled at 0?C in ice-water bath. Ethyl
chloroformate (25 mmol, 2.7 g) was added dropwise to the mixture while keeping
the temperature at 0?C. After 15 min stirring at this temperature, a solution
of compound V (25 mmol, 3.6 g) in dried chloroform as well as dried
triethylamine (5.0 g) were added gradually to the mixture and the reaction was
left for 30 min at room temperature and then refluxed for 10 min at 50?C. The reaction
mixture was then washed several times with water and sodium hydrogen carbonate
solution (0.5M). After solvent evaporation, a yellow solid was obtained which
following chromatography on silica gel gave the product as an oily compound:
For (methyl derivative) : yield 68 %, IR(CHCl3): ν
1740, 1700 cm-1 (C=O)
To a hydroethanolic solution of VI (6.73
mmol), sodium hydroxide (10%, 30 ml) was added. The mixture was refluxed for 30
min. Ethanol was removed by evaporation and the residue was pH adjusted to
5-5.5. Saturation with NaCl and extraction by chloroform-isopropanol (10:1),
gave an oily product after solvent evaporation: yield 77-85%;
IR(CHCl3): ν
3440 (OH), 1700, 1680 cm-1 (C=O). Elemental microanalyses were
within ? 0.4% of the theoritical values for C, H, N.
Results and Discussion
In molecular designing of some imidazole
derivatives of captopril, the designed structures had the main captopril pharmacophores.
In order to confirm whether the designed compounds could mimic proper
conformation for binding to ACE, they were superimposed on captopril molecule.
Superimposition of energy minimized conformers showed that the main proposed
pharmacophores i.e. carboxylic, carbonyl and mercapto groups were well matched
with captopril functional groups. Moreover, the addition of alkyl groups on the
terminal SH did not interfere with superimposition. It should be mentioned that
alkylation makes the molecule more tight binding to ACE (2) as well as more
lipophilic so that potency along with oral absorptivity of the synthesized
molecules can be increased.
In captopril molecule the SH group has a key
role in the interaction with zinc ion of ACE (2). However, the alkylthio group
on the designed molecules should play that role since the lone pair electrons
of sulfur atom is still available. On the other hand, the alkylthio is not
expected to produce side effects like the free SH group on captopril molecule.
This study also showed that the synthesis strategy for the imidazole
derivatives of captopril, as depicted in Scheme 1, is quite applicable. That is
because it consists only few steps which are feasible and afford overall
acceptable yields.
The present new imidazole derivatives of
captopril are promising to give more potent ACEI compounds with better oral
bioavailability. However, in vitro binding assay on purified ACE as well
as in vivo experiments on animals are needed to prove such expectation.
Acknowledgments
This research was supported by a grant from
the deputy for research of Shaheed Beheshti University of Medical Sciences,
Iran.
References
Garrison JC and
Peach MJ. Renin and angiotensin. In: Goodman Gilman A, Rall TW, Nies AS and
Taylor P (Eds.) The Pharmacological Basis ofTherapeuticsVol.1. 8th ed, Pergamon Press (1991) 749-763
Harrold M.
Angiotensin converting enzyme inhibitors, antagonists and calcium blockers. In:
Williams DA and Lemke TL (Eds.) Foye's Principlesof Medicinal
Chemistry. 5th ed, Lippincott Williams & Wilkins (2002)?
533-561
Patchett AA,
Harris E. and Tristram EW. A new class of angiotensin-converting enzyme
inhibitors. Nature (1980) 288: 280-283
Krapcho J, Turk
C, Cushman DW, Powell JR, DeForrest JM, Spitzmilker ER, Karanewesky DS, Duggan
M and Rovnyak G. Angiotensin converting enzyme inhibitors, Mercaptan,
carboxyalkyl dipeptide and phosphinic acid inhibitors in corporating
4-substituted prolines. J. Med. Chem. (1988) 31: 1148-1160
Marie-Claude
FZ, Pascale C, Vincent T, Walter G, Herve M, Serge T, Jean-Baptiste M and
Bernard PR. Design of orally active dual inhibitors of neutral endopeptidase
and angiotensin-converting enzyme with long duration of action. J. Med. Chem
(1996) 39: 2594-2608
PCMODEL; Serena
software: P.O. Box 3070, Bloomington, IN 47402, USA
Shafiee A,
Zarghi A and Dehpour A.R. Synthesis and Anti-infammatory activity of
1-methyl-2-(4-X-benzyl) pyrrolo[2,3-d] imidazole-5-carboxylates. Pharm. Sci.
(1997) 3: 461-463
Shafiee A,
Ebrahimzadeh, A, Zarghi A and Dehpour A.R. Synthesis and Anti-infammatory
activity of 1-benzyl-2-(X-thio) pyrrolo[2,3-d] imidazole-5-carboxylates. Pharm.
Pharmacol. Commun.( 1998) 4: 99-101
March J. Advanced
Organic Chemistry. 3rd ed. Willey limited (1994) 652-653
Doo H,
Nam-Choon SL and Dewey DYR. An improved synthesis of captopril. J. Pharma.
Sci. (1984) 73: 1843-1844
Klutechko S,
Blankley CJ, Fleming RW, Hinkley JM, Werner AE, Nordin I, Holmes A, Hoefle ML,
Cohen DM, Essenburg AD and Kaplan HR. Synthesis of novel angiotensin converting
enzyme inhibitor quinapril and related compounds; J. Med. Chem. (1986)
29: 1953-1961
Shimazaki M,
Hasegawa J, Kan K, Nomura K, Nose Y, Kondo H, Ohashi T and Watanabe KM.
Synthesis of captopril starting from an optically active β-hydroxy
acid. Chem. Pharm. Bull. ( 1982) 30: 3139-3146
Furniss BS,
Hannaford AJ, Rogers V, Smith PWG and Tatchell AR. (Eds) Vogel's Textbook of
Practical Organic Chemistry, 5th ed, John Willey & Sons,
Inc. (1989)? 761-1912