Pharmaceutical Chemist~3' Journal
5, 1999
SEARCH FOR NEW DRUGS
BENZIMIDAZOLE DERIVATIVES: SPECTRUM
OF PHARMACOLOGICAL ACTIVITY
AND TOXICOLOGICAL PROPERTIES (A REVIEW)
A. A. Spasov, 1 I. N. Yozhitsa, t L. I. Bugaeva, ~ and V. A. A n i s i m o v a t
Translated from Khimiko-Fannatsevticheskii Zhurnal, Vol. 33, No. 5, pp. 6 - 17, May, 1999.
Original article submitted Janual T 3, 1998.
The properties of benzimidazole and its derivatives have
been studied over more than one hundred years [1]. However,
a special interest of researchers toward this class of com-
pounds was stimulated by the fact that 5,6-dimethylbenzimi-
dazole is a component of vitamin Bi2 [2]. Shortly after, it was
established that, albeit vitamin B~2 is capable of stimulating
the growth of bacteria, the benzimidazole fragment and some
of its derivatives suppress the bacterial growth. This discov-
ery was followed by attempts to create new antibacterial
preparations based on the benzimidazole derivatives.
Antibacterial and antiviral activity. A series of halo-
gen-substituted 5,6-dimethylbenzimidazole derivatives ex-
hibit pronounced antibacterial and antiviral properties [3 - 7].
This is explained by their competition with purines resulting
in inhibition of the synthesis of microbial nucleic acids and
proteins [3, 6 - 8].
Derivatives of pyrimido[ 1,6-a]benzimidazole represent a
new class of DNA-gyrase inhibitors, which are effective an-
tibacterial agents [9]. Antimicrobial and antifungal properties
were reported for 3-alkylthiomethyl-l-ethyl-, 3-alk-
oxymethyl-l-butyl-, and 3-alkylthiomethyl-l-butylbenzimi-
dazolium chlorides, as well as for 2-chloromethyl-5H-
methylbenzimidazoles [10, 1 l]. Some 5-nitrobenzimidazole
derivatives also exhibit fungicidal activity [12]. Certain an-
timicrobial and antifungal potential was observed in hetero-
cyclic benzimidazole derivatives [13].
It was established that 1-(2,6-difluorophenyl)-lH,3H-
thiazolo[3,4-a]benzimidazole (triazobenzimidazole) pro-
duces an antiviral effect by inhibiting the non-nuclear reverse
transcriptase activity [14]. This preparation has proved to be
effective against the H1V-1 infection, the effect resulting
from selective inhibition of the reverse transcriptase of HIV- 1
(but not HIV-2). Sulfoxide and sulfonic metabolites of thia-
1 State Medical Academy, Volgograd, Russia.
232
I/ol. 33, ~)).
zolobenzimidazole, found in the blood and urine of mice, also
showed activity with respect to HIV- 1 [ 15, 16].
Antitumor activity. The class of benzimidazole deriva-
tives contains compounds possessing affinity to DNA. For
example, fluorescent stains of the Hoechst 33342 and 33258
types interact with DNA as ligands [ 17] and produce nonspe-
cific inhibition of the catalytic activity of many enzymes in-
volved in DNA synthesis, including DNA polymerase I [18].
Another promising group of antitumor compounds is repre-
sented by benzimidazo[t,2-c]quinazolines and thiazolo[3,4-
a]benzimidazoles [ 19, 20].
Antimutagen effects. Some benzimidazole derivatives
are capable of correcting the mutagen action of xenobiotics.
For example, bemithyl (2-ethylthiobenzimidazole hydro-
bromide) produced antimutagen effect with respect to diox-
idine, fotrin, and fopurine, as manifested by a decrease in the
frequency of induced chromosome aberrations in the bone
marrow of mice and in a lymphocyte culture of peripheral hu-
man blood [21, 22]. Bemithyl and tomerzole exhibit an anti-
clastogenic action with respect to some corpuscular mutagens
as well [23]. The new benzimidazole derivative 2-(2,3-dihy-
droxyphenyl)-9-(2-diethylaminoethyl)imidazo[1,2-a]benzim
idazole hydrobmmide (AKS-185) decreases the level of cy-
clophosphamine-induced dominant lethal mutations in
Drosophilidae [24].
Antihelminth activity. Original results of investigations
devoted to the antihelminth properties of benzimidazole de-
rivatives were published within the time period from the mid-
dle 1960s to the beginning 1970s. One of the first drugs rep-
resenting these compounds, now widely used in helminthol-
ogy, was mebendazole [25 - 30].
An original domestic antihelminth drug, approved and al-
lowed for wide clinical use, is medamine synthesized at the
Martsinovskii Institute of Medical Parasitology [31].
0091-150X/99/3305-0232522.00 9 1999 KluwcrAcademic/Plenum Publishers
Benzimidazole Derivatives: Spectrum of Pharmacological Activity and Toxicological Properties
At present, more than twenty benzimidazole derivatives
are used as antihehninth preparations in the world veterinary
and medical practice, including thiabendazole [ 3 2 - 38], ox-
fendazole [37 - 43], albendazole [44 - 46], fenbendazole [38,
41,45, 46], triclabendazole [47-49], oxibendazole [37, 38,
43, 45, 46, 50], cambendazole [38, 50], parbendazole [38],
nocodazole [45], luxabendazole [51,52], flubendazole [43],
etc. The antihehninth activity was also found in some deriva-
tives of 3-(benzimidazol-2-yl)-2-propenoic acid and
2-methoxycarbonylamino-5-(4-salicyloylpiperazin- 1-yl)benz-
imidazole [53, 54].
Mechanisms of the antihelminth activity of these prepara-
tions are yet insufficiently studied. It was suggested that the
benzimidazole derivatives may selectively and irreversibly
inhibit the absorption of glucose by helminths and produce
degenerative changes in the intestinal tract of nematodes and
in the absorptive cells of cystodes. Apparently, the principal
antihelminth effect consists in degeneracy of the cytoplasmic
microtubules inside the intestinal and absorptive ceils of a
parasite, which hinders the motion of its organelles [55]. This
results in accumulation of excess intracell secretory granules
leading to autolysis of the cells under the action of hydrolytic
and proteolytic enzymes, which kills the parasites [55].
Cardiovascular effects. In the 1940s, a group of re-
searchers including Porai-Koshits, Ginzburg, and Efros syn-
thesized 2-benzylbenzimidazole [56], which was capable of
decreasing the tone of smooth muscles of the blood vessels and
internal organs. This compound, called dibazole, is widely used
as a spasmolytic and hypotensive remedy [57 - 63].
A pronounced antihypertensive activity is characteristic
of a series of compounds including TCV-116, BtBR 277,
BIBS 39, BIBS 222, CV-11194, and C V - 1 1 9 7 4 (see Ta-
ble 1). The mechanism of their action is related to a selective
antagonism to the angiotensin II receptors [ 6 4 - 68]. Another
interesting compound is Ro 4 0 - 5 9 6 7 , which is capable of
blocking calcium channels [69 - 73].
A systematic search for active compounds in the series of
imidazo[l,2-a]benzimidazole derivatives [74-81] led to
substances possessing antiarrhythmic properties [82, 83], in-
creasing the antihypoxic stability of myocardium [84], and
enhancing the nonspecific resistance of the heart and the en-
tire organism with respect to stressor damage [85, 86].
The maximum antiarrhythmic activity among the sub-
stances studied was observed for 9-(2-diethylaminoethyl)-2-
tert-butylimidazo[l,2-a]benzimidazole dihydrochloride (rit-
midazole) [76 - 81 ], which is a calcium antagonist acting si-
multaneously upon the incoming sodium ad outgoing potas-
sium currents, and the compound AKS-185. The latter com-
pound exhibited a number of additional properties: produced
an antioxidant effect, limited the zone of necrosis on the ex-
perimental myocardial infarction model, improved the sur-
vival of rats upon ligation of both carotid arteries [87, 88],
enhanced the cerebral blood flow, increased the resistance of
experimental animals with respect to circulatory hypoxia, im-
proved the course of the postischemic period and suppressed
development of the related cerebrovascular phenomena, and
233
restored violated parameters of the oxidative and transcapil-
lary metabolism [88].
The compound AKS-180, or 2-(3,4-dimethoxyphenyl)-
(13-diethylaminoethyl)imidazo[ 1,2-a]benzimidazole nitrate,
also produced a maximum positive effect upon the stability of
myocardium with respect to hypoxia: the drug restricted
myocardial damage related to an oxygen deficiency caused
by isadrine intoxication or coronary occlusion [82, 83]. The
antihypoxic effect of AKS-180 was explained by its ability to
increase the cAMP level and the antioxidant properties
[82, 83].
Blocking of the proton pump (H+/K+-ATPase) in pa-
rietal cells of the stomach. Some of the benzimidazole de-
rivatives effectively suppress the proton pump function of pa-
rietal cells of the stomach, thus blocking the final stage of hy-
drochloric acid secretion [89-92]. All compounds of this
group are weak bases and exhibit no effect in a neutral me-
dium. However, an acid medium in the channels of parietal
cells transforms these compounds into an active metabolite.
This metabolite is capable of binding to the membrane
H+/K+-ATPase by forming disulfide bridges, thus irre-
versibly inhibiting the enzyme [89]. The most known drugs
of this group, representing 2-(2-pyridylmethylsul-
finyl)benzimidazole derivatives, are omeprazole [89-94],
pantoprazole [ 9 5 - 101], lansoprazole [100, 1 0 2 - 104], lemi-
noprazole [104- 107], timoprazole [90, 91], and picoprazole
[91,93] (Table 1). Antisecretory and antiulcerous activity
was also reported for the compounds AKS-13 and AKS-63
representing 9-(2-diethylaminoethyl)-2-phenylimidazo[ 1,2-a]-
benzimidazole dihydrochloride and dihydrobrornide, respec-
tively [75, 108].
Antiallergic activity. The group of effective long-action
blockers of the Hrhistamine receptors includes astemizole
[109-115], mizolastine [116-120], emidastine [121,122],
and clemizole [111] (Table 1).
Analgesic, antiiflammatory, and antipyretic activity.
In recent years, much effort was devoted to studying the anal-
gesic drug etonitazene- a compound selectively interacting
with opiate receptors of the ~t-subtype [ 1 2 3 - 127]. The anal-
gesic and antiinflammatory activity was observed in some de-
rivatives of 3-(benzimidazol-2-yl)propanoic acid [128] and
2-aminobenzimidazole [129]. It was also reported that the an-
tihelminth drug thiabendazole produced antiinflammatory,
antipyretic, and analgesic effects [ 130].
Some of the benzimidazole derivatives possess selective
antiinflammatory and antipyretic activity [ 131 ]. For example,
an antiinflammatory activity of this type was observed for the
immunomodulant WY-18251, or 3-(p-chlorophenyl)thia-
zolo[3,2-a]benzimidazole-2-acetic acid [ 132, 133].
It was reported that bemithyl is an effective drug for the
complex treatment of some inflammatory and infectious dis-
eases [134-t40]. According to other data, dibazole is also
capable of reducing the intensity of both aseptic [141 - 143]
and infectious [144, 145] inflammatory processes. Some of
the benzimidazole and imidazobenzimidazole derivatives
234 A . A . Spasov et al.

TABLE i. Types of Pharmacological and Biological Activity of Benzimidazole Derivatives

Activity Drug name (code) Chemical formula Refs.
Cholinolytic Pimozide 1-[ I-[4.4-Bis(4-fluorophenyl)butyl]-4-piperidinyl]- 1,3-dihydro-2H- [180. 246 - 248]
benzimidazol-2-one
Dopaminergic action:
D 2 receptor antagonist Pimozide [ 180 - 185]
Domperidone 5-Chloro-I-[l-[3-(2,3-dihydro-2-oxo- I H-benzimidazol-1- [I 70 - 177]
yl)propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one
DAU 6215 (BIMU-8) s I ]oct-3-yl)-2,3-dihydro-2-oxo- [210, 249]
I H-benzimidazole- I -carboxamide hydrochloride

Serotoninergic action:
5-HT 3 receptor antagonist DAU 6215 (BIMU-8) [210, 249]
BIMU-1 Endo-N-(8-methyl-8-azabicyclo[3.2.I ]oct-3-yl)-2,3-dihydro-3- [250]
ethyl-2-oxo- I H-benzimidazole- 1-carboxamide hydrochloride
YM 060 (R)-5-[(1-Methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1 H- [25 I]
benzimidazole hydrochloride
YM 114 (KAE-393) (R)-5-I(2,3-Dihydro- I -indolyt)carbonyl]-4,5,6,7-tetrahydro- 1H- [251]
benzimidazole hydrochloride
5-HT4 receptor antagonist DA U 6285 2,3-Dihydro-6-methoxy-2-oxo- I H-benzimidazole- t -carboxylic [252 - 254]
acid endo-8-methyl-8-azabicyclo[3.2, t ]oct-3-yl ester hydrochloride
l~-Adrenomimetic (bronchotytie) CG P-12177A 4-[3-[( 1,1 -dimethylethyl)amino]-2-hydroxypropoxy]- 13-dihydrn- [255,256]
2H-benzimidazol-2-one hydrochloride
r Pimozide [180 - 182]
GABA-mimetic -- Pyrido[ 1,2-a]benzimidazole derivatives [164]
Striated neurokinin- [ receptor WIN 51708 [ I R-( 1a3al3.3bct,5a[3,15aa, 15b[3 17aa)]- 1-Ethynyl- [257 - 259]
antagonist 2,3,3a,3b,4,5,5a,6,15,15a, 15b, 16,17,17a-tetradecahydro- 15a, 17a-
dimethyl- 1H-benzimidazo[2,1 -b]cyclopenta[5,6]naphtho[ 12-
d]quinazolin-l-ol
17[3-Hydroxy- 17ct-ethynyl-5ct-androstano[3.2-b]pyrimido[ 1,2-ct] [257-259]
benzimidazole
Antihistamine (antianaphylactic) Astemizole 1-[(4-Fluorophenyl)methyl]-N-[ I -[2-(4-methoxyphenyl)etbyl]-4- [109-115]
(hismanal) piperidinyl]- 1H-benzimidazole-2-amine

Mizolastine 2-[[1-[ l-[(4-Fluorophenyl)methyl]-I H-benzimidazol-2-yl]-4- []]6-]20]

piperidinyl]methylamino]-4-( 1H)-pyrimidinone
Emidasline 1-(2-Ethoxyethyl)-2-(4-methyl-1-homopiperazinyt)benzirnidazole [121.122]
difumarate
Proton pump (H+/K+-ATPase) Omeprazole 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2- [89-94]
inhibitor: gastric gland secretion pyridinyl)methyl]sulfinyl]- 1H-benzimidazole
suppressor
Pantoprazole 5-Difluoromethoxy-2-[[(3,4-dimethoxy-2- [95-]0U
pyridinyt)methyl]sulfinyl]- 1H-benzimidazole
keminoprazole ( _+)-2-[[2-(Isobutylmethylamino)benzyl]sulfinyl]-t H- 1104-107J
(NC- 1300-O-3) benzimidazole
Antihypertcnsive action:
Angiotensin AT 2 receptor TCV-116 2-Ethoxy-l-[[2'-( I H-tetrazol-5-yl)[ 1,I-biphenyl]-4-yl]methyl]- 1H- [64. 65, 67, 68]
antagonist benzimidazole-7-earboxylic acid ( +_)-I-
[[(cyclohexyloxy)carbonyl]hydroxy]ethyl ester
BIBR 277 4'-[( 1.4'-Dimethyl-2'-propyl)-[2,6'-bis- I H-benzimidazol- I '- [65]
yl]methyl]- 1, I '-biphenyl]-2-carboxylic acid
BIBS 39 4'-[[2-(n-Butyl)-6-[[(cyclohexylamino)carbonyl]amino]- l H- [65]
benzimidazol- 1-yl]methyl]-[1,1 -biphenyl]-2-carboxylic acid
BIBS 222 2-[[[4-[[2-Butyl-6-[[(methylamino)carbonyt]pentylamino]- I H- [651
benzimidazol- l-yl]methyl]phenyl]amino]carbonyl]-3,6-
dichtorobenzoic acid
CV-11194 2-Butyl- 1-[[2'-( 1H-tetrazol-5-yl)[ I, 1'-biphenyl]-4-yl] methyl]- I H- [65. 66]
benzimidazole-7-carboxylic acid
CV-II974 2-Ethoxy- 1-[[2'-( I H-tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl] methyl]- [65.66]
1H-benzimidazole-7-carboxylic acid
Spasmolytic (direct myotropic effect) Dibazole(tromasedan) 2-Benzylbenzimidazole [57 - 63]
Benzimidazole Derivatives: Spectrum of Pharmacological Activity and Toxicological Properties 235

TABLE I. (Continued)
Acti,,ity Drug name (codc) Chemical fomlula Refs.
Ca 2+ channel blocker Ro 40 - 5967 Methoxyacetic acid ( 1S,2S)-2-[2-[[3-( 1H-benzimidazol-2- [69 - 73]
yl)propyl]methylamino]ethyl]-6-fl uoro-1,2,3,4-tetrahydro-I-
isopropyl-2-naphthyl ester hydrochloride
+
CaZ+-dependent K channel activator NS-4 l-(5-chloro-2-hydroxyphenyl)-5-trifluoromethyl- t ,3- [260 - 262]
dihydrobenzimidazol-2-one
NS-1619 1-(2-hydroxy-5-trifluoromethylphenyl)-5- [26], 263]
trifluoromethylbenzimidazol-2(3 H)-one
Antiaggregant Dibazole [150]
Thromboxane A 2 receptor antagonist KW-3635 (E)- I I -[2-(5,6-dimethyl- l-benzimidazotyl)ethylidene]-6, I 1- [264 - 268]
dihydrodibenz[b,e]oxepine-2-carboxylate sodium monohydrate
Anxiolytic (tranquilizer) Ethomerzole 5-Ethoxy-2-ethylbenzimidazole hydrochloride [ 165 - 167]
Bemithyl 2-Ethytbenzimidazole hydrobromide [ 165 - 167]
- - Pyrido[ 1,2-a]benzimidazole derivatives [ 164]
-- 1-Vinytbenzimidazole hydrochloride [ 168]
Neuroleptic (antipsychotic) Domperidone [I 70 - 173]
Pimozide [ 170 - 173]
Anticonvulsant Dibazole [I 61 ]
- - Thiazolo[3,2-a]benzimidazole derivatives [I 63]
Analgesic and antiinflammatory gtonitazene 2-[(4-Ethoxyphenyl)methyl]-N,N-diethyl-5-nitro-1 H- [ 123 - [ 27]
benzimidazole-l-ethanamine
2-Amino- I H-benzimidazole [129]
3-( 1H-Benzimidazol-2-yl)propanoic acid derivatives [1281
WY-18251 3-(4-Chlorophenyl)thiazolo[3,2-a]benzimidazole-2-acetic acid [132, 133]
Antihelminth Mebendazole 5-Benzoyl-2-methoxycarbonylaminobenzimidazole [25-301
Medamine ( I H-Benzimidazol-2-yl)carbamic acid methyl ester [31]
3-(1H-Benzimidazol-2-yl)-2-propenoic acid derivatives [53]
2-Methoxycarbonylamino-5-(4-salicyloylpiperazin-l-yl)- [541
benzimidazole
Antiviral and antimicrobial NSC 625487 I -(2,6-Difluorophenyl)- I H,3 H-thiazolo[3,4-a]benzimidazole [ 1 4 - 161
Fungicide 5-Nitrobenzimidazole derivatives [13]
2-Chloromethyl-5 H-methylbenzimidazole derivatives [lo, ll]
Antitumor Thiazolo[3,4-a]benzimidazole derivatives [i9]
Benzimidazo[ 1,2-c]quinazoline derivatives [20]
Adaptogen and actoprotector Dibazole [i58]
Bemithyl [194 2011
Ethomerzole [199]

(RU-13, RU-63) exceed dibazole with respect to antiiflam-
matory activity, showing an effect comparable to that ofami-
dopyrine [ 137].
Hypoglycemic effect. The condensed benzimidazole de-
rivative 9-(2-diethylaminoethyl)-2,3-dihydroimidazo[1,2-
a]benzimidazole dihydrochloride (diabenol) was reported to
possess hypoglycemic and antiaggregant properties [146,
147]. The hypoglycemic effect of this compound, observed
both on intact animals of various kinds and on test animals
with experimental alloxan-induced diabetes, was related to its
effect upon insulin secretion, enhancement of the glucose
utilization in peripheral tissues, and prolongation of the hypo-
glycemic action of insulin [ 147 - 149].
Antiealmodulin action. An important role in Ca2+ ion
activity regulation belongs to the calcium-binding protein
calmodulin. The Ca2+-calmodulin complex affects the ac-
tivity of many enzymes, thus influencing biochemical func-
tions of the cells.
It was shown that some imidazobenzimidazole deriva-
tives possess pronounced anticalmodulin activity. For exam-
ple, N i, N9-derivatives of imidazo[1,2-a]benzimidazole, as
well as 2,3,4,10-tetrahydropyrimido[l,2-a]pyrrolo[l,2-a]-,
pyrazolo[1,5-a]-, triazolo[2,3-a]-, and triazino[1,5-a]benzimi-
dazoles, inhibit to various extents the calmodulin activity.
The maximum anticalmodulin effect was observed for imi-
dazo[l,2-a]benzimidazoles containing a 13-dimethylami-
noethyl group at the N9 nitrogen atom and a methoxyphenyl
radical at the C2 carbon atom [148, 149].
Antiaggregant action. Diabenol is capable of inhibiting
platelet aggregation induced by ADP, adrenalin, collagen,
PAF, and arachidonic acid, which is explained by suppres-
sion of the synthesis of thromboxane A2. It was reported that
236
diabenol not only influences the aggregation process, but pro-
duces a certain deaggregating effect as well [146, 147].
The antiaggregant properties were also observed for diba-
zole [150], the antihelminth drug nocodazole [151], and
ethomerzole (5-ethoxy-2-ethylthiobenzimidazole) [152-
154].
Action upon CNS. Some benzimidazole derivatives pro-
duce various, in both type and strength, effects upon the cen-
tral nervous system, including psychostimulant, neuroleptic,
antidepressant, tranquilizer (anxiolytic), anticonvulsant, and
hypnotic action.
It was shown that dibazole and 5,6-dimethylbenzimida-
zole (dimedazole, dimezole) are capable of eliminating some
neurological disorders accompanying experimental brain
traumas and can be used for the prophylaxis of pain shock
[155-160].
Anticonvulsant properties were reported for dibazole
[16l], plain benzimidazole [162], and thiazolo[3,2-a]-
benzimidazole [ 163].
The anxiolytic activity was observed in pyrido[1,2-a]-
benzimidazole derivatives, which are capable of interacting
with benzodiazepine receptors associated with GABA A-re-
ceptors [164]. Indeed, stimulation of the benzodiazepine re-
ceptors leads to allosteric activation of the GABA A-recep-
tors. For this reason, the interaction of pyrido[1,2-a]benzimi-
dazoles with the benzodiazepine receptors is manifested by
the GABA-mimetic effect [164]. A single administration of
bemithyl, ethomerzole (5-ethoxy-2-etbylthiobenzimidazole
hydrochloride), and 2-phenylthio-6-ethylbenzimidazole hy-
drobromide also produced an anxiolytic action not accompa-
nied by sedative (calming) effects [165 - 167].
1-Vinylbenzimidazole hydrochloride exhibits anxiolytic
activity, increases the working capacity, and produces an an-
tioxidant effect [ 168].
Some 2-aminobenzimidazole derivatives, including N-
(l-butylbenzimidazol-2-yl)succinamic acid propylamide and
N-( l-benzylbenzimidazol-2-yl)succinamic acid benzylamide,
suppressed the behavioral activity of experimental animals,
increased ethaminal-induced sleep, and produced other ef-
fects characteristic of aminazine [ 169].
Pronounced antipsychotic properties were observed for
domperidone (see Table 1), which is a selective antagonist of
the D2-dopamine receptors (much less active with respect to
the D i subtype of dopamine receptors) [170 - 173]. Domperi-
done also produced an antiemetic effect related to its block-
ing action upon the peripheral dopamine receptors. This ac-
tion eliminates the inhibiting effect of dopamine on the motor
function of the gastrointestinal tract and increases the evacu-
ation and motor activity of the stomach [ 174 - 177].
The antipsychotic drug pimozide, containing a benzimi-
dazole fragment (otherwise structurally close to butyrophe-
nones) [ 178 - 180], has a wide spectrum of pharmacological
activity similar to that of haloperidol and, to a lesser extent,
phenothiazines [ 180 - 184].
Pimozide is capable of inhibiting the release of dopamine
induced in vitro by electric depolarization of membranes in
A . A . Spasov et al.
the brain tissue [185] and enhances dopamine synthesis and
circulation in the brain [186, 187]. The effect of pimozide on
other catecholamines is less pronounced [181,182, 186,
187]; also high doses of this drug can increase the circulation
of noradrenaline in the brain [ 181, 182, 187].
In the human organism, pimozide reduces amphetamine
induced euphoria [188] and arrests anxiety manifestations in
schizophrenes and patients with psychic disorders of a neu-
rotic type [ 189 - 191 ].
The exact mechanism of the antipsychotic action of pi-
mozide is not yet established. Some researchers believe that
the effect can be related to the antidopaminergic activity of
this compound [180, 181,183- 185].
It was suggested that pimozide is a selective antagonist of
the D2-dopamine receptors [184], which can indirectly (via
antidopaminergic action) decrease the content of acetyl-
choline in the brain. However, in this respect pimozide is less
active compared to the other known antipsychotic drugs [ 180].
Pimozide was also reported to produce an antiemetic ef-
fect mediated by chemoreceptors of the trigger zone, which is
probably explained by blocking of the corresponding
dopamine receptors [ 192].
Adaptogen and actoprotector effects. Some benzimida-
zole derivatives not only increase working capacity upon pre-
liminary administration, but restore working capacity after
intensive physical loading as well. For example, dibazole is
capable of increasing and accelerating various processes of
long-term adaptation [158]. This drug was considered as one
of the first representatives of a then new class of pharma-
cological substances introduced by N. V. Lazarev and called
adaptogens. However, according to some other data [193],
dibazole rather weakly affects the physical endurance upon a
single administration.
A series of 2-mercaptobenzimidazole derivatives synthe-
sized later showed the ability to accelerate restoration of
working capacity under complicated environmental and op-
erational conditions. It was suggested to classify these com-
pounds as a special group of drugs called actoprotectors [194
- 199]. By now, the best studied actoprotectors are bemithyl
and ethomerzole.
Bemithyl is an effective remedy accelerating restoration
of working capacity [194, 195]. The restoring effect is more
pronounced than an increase in the working capacity during
an intellectual activity or physical activity [196]. These prop-
erties explain the efficacy of bemithyl in the therapy of as-
thenic states related to boundary nervous-psychic disorders.
Bemithyl is also used for prophylaxis and blocking of psy-
chogenic reactions in critical situations [200, 201].
A mechanism ofbemithyl action is based on activation of
RNA synthesis as a result of the drug-genome interaction
facilitated by certain structural similarity between the
benzimidazole derivatives and the purine bases of nucleic ac-
ids (adenine and guanine) [194, 195, 197]. Bemithyl is not a
primary activator of particular genes: the drug only produces
a nonspecific acceleration of the RNA synthesis in various
tissues. This results in activation of the production of pro-
Benzimidazole Derivatives: Spectrum of Pharmacological Activity and Toxicological Properties
teins, among which the most important are a series of short-
living proteins including the gluconeogenesis enzymes. Ac-
cording to modem notions, the short-living proteins may play
a key role in the adaptation-dysadaptation processes,
whereby a rapid preferential synthesis of these substances ac-
counts for the initial adaptation manifestations, while an early
decrease in their content in tissues starts up the corresponding
dysadaptation changes [ 194, 195, 197, 202, 203].
Important components in the mechanism of bemithyl ac-
tion are decreased oxygen demand and reduced heat evolu-
tion in the organism. There are data that the drug suppresses
some pathways of free nonphosphorylating oxidation and
maintains mitochondria in a more conjugated state. These ef-
fects, which are especially pronounced upon the action of fac-
tors (e.g., under heavy physical loading) leading to separation
of the oxidation and phosphorylation processes, are due to a
protective action of the drug on the structure ofmitochondria.
This protective action can be partly related to enhanced syn-
thesis of the components of mitochondrial membranes [194,
195, 197]. The protective action of bemithyl upon mitochon-
drial membranes is sometimes additionally manifested by in-
hibited peroxidation [204].
Investigation of the adaptogen and actoprotector proper-
ties of a large series of imidazo[l,2-a]benzimidazole deriva-
tives revealed a group of the most active compounds includ-
ing 9-(2-piperidinoethyl)-2-(4-hydroxyphenyl)imidazo[1,2-
a]benzimidazole hydrochloride (AKS-87), 9-(2-diethylami-
noethyl)-2-(4-hydroxyphenyl)imidazo[1,2-a]benzimidazole
hydrobromide (AKS-85), and AKS-I 8. The compound AKS-
87, which is the least toxic in this group, improves the work-
ing capacity of mice in the swimming test, increases the sur-
vival of test animals under the action of unfavorable factors
(radial acceleration, adrenaline or strychnine intoxication,
and hypercapnial, histotoxic, or hypoxic hypoxia), and effec-
tively protects myocardium against stressor action [85]. The
compounds AKS-185, AKS-85, and AKS-87 led to a pro-
nounced increase in the working capacity as manifested by the
test of swimming under normoxic and hypoxic conditions [205].
Antihypoxic and antioxidant activity. Ethomerzole ex-
hibited a protective effect in tests on animals having different
degrees of resistance with respect to hypoxic states and accel-
erated the restoration of behavioral, dynamometric, locomo-
tor, and mnestic characteristics in animals upon hypoxic
trauma, The compound AKS-185 increased the lifetime of
both low-resistant and high-resistant rats tested under acute
hypobaric hypoxia conditions and accelerated the process of
recovery upon hypoxic and ischemic trauma [206, 207].
Hepatoprotector action. The compound AKS-185 pro-
duces a pronounced protective effect against liver damage in-
duced by tetrachloromethane or D-galactosamine, which is also
related to the antioxidant properties of this drug [208, 209].
Table 1 gives data on the pharmacological activity of
some benzimidazole derivatives, classified with respect to the
receptor and molecular-cellular aspects of their action.
237
An analysis of the published data also reveals the side ef-
fects of benzimidazole derivatives, the main of which are as
follows.
Side and toxic effects upon CNS. A toxic dose of the
compound DAU 6215, which is a selective antagonist of the
serotonin 5-HT3 receptors, was reported to produce CNS exci-
tation and a small tremor passing into a convulsive state [210].
Therapeutic doses of domperidone and pimozide may in-
duce extrapyramidal disorders [211, 181 - 183].
The clinical administration ofpimozide may be accompa-
nied by the development of insomnia, vertigo, motor excita-
tion, neuroses, syncopes, aggression, and erethism and the
appearance of anxiety, headache, depression, incubus, hallu-
cinations, phobic manifestations, and increased fatigability.
There have been infrequent cases of pimozide-induced epileptic
attacks, including tonic-clonic convulsions [ 181 - 183].
Side and toxic effects upon the endocrine system. Ex-
periments on a sample of dispersed glomerular cells of the
adrenal cortex of rabbit showed that the compound CV-116,
which is an antagonist of the angiotensin AT~ receptors, in-
hibits the aldosterone production [212]. The inhalation of 2-
mercaptobenzimidazole by rats led to a hyperplasia of the
adenohypophysis cells, a decrease in the triiodothyronine and
thyroxine in the blood plasma, a hypertrophia and hyper-
plasia of the thyroid follicular cells, and a goiter formation
[213].
Cardiotoxic effects and hemodynamic disorders.
Some of the drugs capable of suppressing the proton pump
(H+/K+-ATPase) function, such as omeprazole, pantoprazole,
and lansoprazole, were reported to induce retrosternal pain,
tachycardia, bradycardia, arrhythmia, and increase in the arte-
rial pressure [214].
Pimozide may sometimes lead to orthostatic hypotension,
hypertension, and tachycardia [ 181 - 183].
It was reported that overdosing with astemizole led to
syncopal states, elongated Q - T intervals in ECG, and ven-
tricular fibrillation [ 110, 112].
Dibazole and its imidazo analog RU-13 may produce a
cardiodepressive effect related to their ability to block the
Ca2+ and Na 2+ channels [82, 83].
Side effects with respect to blood. A prolonged admini-
stration of mebendazole in a therapeutic dose may result in
the development of leukopenia, anemia, thrombocytopenia,
eosinophilia, hematuria, and cylindruria [28,215, 216]. The
administration of pimozide may lead to a hemolytic anemia
[183]. There are data that hematuria frequently accompanies
omeprazole therapy [214].
Side effects with respect to the gastrointestinal tract. It
was reported that a prolonged administration of mebendazole
may lead to the development of vomit and diarrhea. [28].
The administration of pimozide may induce sialism, nau-
sea, vomit, obstipation, and abdominal pain [181 - 183].
The rather infrequent side effects of omeprazole also. in-
clude nausea, vomit, obstipation, tympanism, acid regurgita-
tion, diarrhea, and abdominal pain. The chronic administra-
tion to rats was accompanied by a dose-dependent increase in
238
the number of carcinoidlike stomach tumors and a hyper-
plasia of the enterochromaffinlike cells. No such effects were
observed in the course of a subchronic experiment in the hu-
man organism [89, 91,214].
The administration of domperidone sometimes leads to a
smooth-muscle spasm in organs of the gastrointestinal tract,
xerostomia, and polydipsia. This drug should be administered
with great care in the case of liver and kidney dysfunction [211].
Some benzimidazole derivatives are capable of effec-
tively inhibiting cytochrome P-450, one of the main enzymes
of the liver monooxygenase system. This is primarily valid
for the drugs inhibiting the proton pump (H+/K+-ATPase)
function [95, 97, 102]. For example, omeprazole may slow
down the elimination of drugs metabolized by oxidation in the
liver (in particular, warfarin, diazepam, and difenin) [103,214],
It was reported that 2-ethylbenzimidazole is a weak in-
hibitor of various monooxygenases, while dibazole acts as a
strong inhibitor of these enzymes, showing definite selectiv-
ity with respect to cytochrome P-450 activity and markedly
increasing the hexenal-induced sleep duration [217].
The administration of astemizole may be accompanied by
violated liver function [113, 114], while a prolonged admini-
stration of mebendazole frequently leads to a transitional in-
crease in the concentration of liver transaminases in the blood
serum of patients receiving this drug [145].
Effects upon the reproductive function. In recent years,
a considerable number of works have been devoted to study-
ing the effects of benzimidazole derivatives upon the repro-
ductive function. Experiments on animals showed that 2-mer-
captobenzimidazole at a dose exceeding 40 mg / kg exhibits a
teratogenic and embryotoxic effect, especially during the pe-
riod of formation and development of the nervous and uro-
genital systems [218 - 223].
Carbendazim ( 1H-benzimidazole-2-ylcarbamic acid
methyl ester) and its precursor benomyl produce a negative
action upon the reproductive function of male rats [223-
225]. A prolonged inhalation ofcarbendazim led to detrimen-
tal changes in the functional and morphological charac-
teristics of spennatogenesis in rats [225]. It was demonstrated
that carbendazim and benomyl produced pronounced em-
bryotoxic [226] and teratogenic [227, 228] effects in various
stages of fetation in rats.
Mebendazole at a dose of 10 m g / kg was also reported to
produce an embryotoxic and teratogenic effects in rats; it was
pointed out that this drug may lead to embryotoxic and terato-
genic effects in pregnant women as well as to a damage of
testicles in men, although these phenomena develop only
upon a prolonged administration of mebendazole [216].
Experiments on sheep, rats, and rabbits showed that ad-
ministration of the antihelminth drug parbendazole at a dose
of 60 m g / k g led to disorders in fetal development [229].
Study of the effects of pimozide at a dose exceeding
2.5 m g / kg (eight times the maximum recommended clinical
dose) upon the reproductive function showed decreased fer-
tility index, increased resorption, and retarded fetal develop-
A.A. Spasov et al.
ment [181 - 183]. Rabbits receiving the drug at these doses
exhibited increased lethality, a decrease in body weight gain,
and various embryotoxic effects (including fetus resorption)
[181- 183].
It was reported that some of the patients receiving pimoz-
ide were subjected to side effects in the form of amenorrhea
or dysmenorrhea, decreased libido, and the development of
impotence [181 - 183]. Similarly to the other antipsychotic
drugs, pimozide increases the concentration of prolactin in
the blood plasma [181,183]. Domperidone was also reported
to increase the prolactin level in the blood plasma and to in-
duce galactorrhea and gynecomastia [211 ].
Rats receiving omeprazole at a dose of 69 mg / kg (170
times the clinical dose) showed evidence of an embryotoxic
effect (increased frequency of fetus resorption and abortion proc-
esses) and retarded postnatal development &the brood [214].
A scheduled introduction of bemithyl at a dose of 20 or
200 m g / kg to rats (during a single cycle of spermatogenesis
in males and four cycles of ovogenesis in females) also ex-
hibited a negative effect upon the reproductive function. The
males showed a decrease in the total amount and mobility of
spermatozoa and an increase in their pathological forms,
while the females showed a decrease in the number of pri-
mordial follicles and follicles having two or more layers
[230].
Investigation of the long-term effects of bemithyl upon
coupling and brood development in rats showed a dose-de-
pendent decrease in the fertility of males and an increase in
the fertility of females, with the absence of any evidence of
toxicity manifestations in the brood [230 - 232].
Mutagen and carcinogen effects. Plain benzimidazole
produces no mutagen effect upon Drosophila melanogaster
[233], while being a mutagen for Salmonella ~'phimurium
[234]. Data available in the literature concerning the mutagen
properties of various benzimidazole derivatives are rather
contradictory.
For example, sulfonyl- and thiocarbonyl-substituted
benzimidazole derivatives are capable of inducing recessive
lethals in drosophila [235]. According to some data, carben-
dazim exhibits a mutagen activity in the Ames test [236,
237], in the micronucleus test on mice [238], and with respect
to the bone marrow cells of rats [239]. In addition, this drug
produces a cytogenetic action upon the peripheral blood cells
of experimental animals [31,240] and mammalian cells in vi-
tro [239]. It was reported that thiabendazole, carbendazim,
and mebendazole exhibited activity in the micronucleus test
on human lymphocytes in vitro [241].
On the contrary, bemithyl studied in a wide dose range
exhibited mutagen properties neither when tested for chromo-
some aberrations in vitro or in vivo or for dominant lethal mu-
tations, nor when studied by the Muller-5 or the somatic
mosaicism techniques [242, 243]. Moreover, the drug even
showed evidence of some antimutagen activity [21, 22, 242, 243].
In experiments on female rats, the peroral introduction of
pimozide (0.62, 5, or 40 m g / kg) for 18 months led to an in-
Benzimidazole Derivatives: Spectrum of Pharmacological Activity and Toxicological Properties
crease in the frequency o f hypophysis adenoma, cell hyper-
plasia, and m a m m a r y adenocarcinoma [ 173 - 175].
Effect upon the cell tubulin system. As noted above, the
fungicidal and antihelminth action o f some benzimidazole
derivatives is apparently related to their ability to induce de-
generacy o f the cytoplasmic microtubules [55], which implies
that the cytotoxic action o f these compounds can be indirectly
related to this effect as well.
The in vit~v investigations showed that carbendazim, me-
bendazole, oxibendazole, and oxfendazole can bind to tubulin
from the rat brain [244]. Study o f the effects o f albendazole,
mebendazole, and thiabendazole upon differentiating tissues
performed on microcell cultures o f rat embryo midbrain and
extremities showed that these compounds effectively inhibit
tubulin polymerase activity in the embryo brain [244]. The
immunofluorescent staining o f the cell culture o f embryo ex-
tremities by anti-13-tubulin monoclonal antibodies indicated
that these drugs produce a decrease in the rate of mitosis
[245].
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