European Journal of Medicinal Chemistry 143 (2018) 232e243

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Mini-review

Recent developments in anti-Trichomonas research: An update review

Veenu Bala a, *, Yashpal S. Chhonker b, **
a
Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, 313001, India
b
College of Pharmacy, Department of Pharmacy Practice, University of Nebraska Medical Centre, Omaha, USA

a r t i c l e i n f o a b s t r a c t

Article history: Trichomonas vaginalis is a major non-viral sexually-transmitted infection resulted into serious obstetrical
Received 26 July 2017 and gynecological troubles. The increasing resistance to nitroimidazole therapy and recurrence makes it
Received in revised form crucial to develop new drugs against trichomoniasis. Over the past few years, a large number of research
9 November 2017
articles highlighting the synthetic and natural product research to combat Trichomonas vaginalis have
Accepted 10 November 2017
Available online 13 November 2017
been published. Electronic databases were searched to collect all data from the year 2006 through June
2017 for anti-Trichomonas activity potential of synthetic and natural products. This review article put
together the synthetic and natural product research to find out an effective metronidazole alternative to
Keywords:
Trichomonas vaginalis
cure trichomoniasis.
Metronidazole (MTZ) © 2017 Elsevier Masson SAS. All rights reserved.
MTZ susceptible
MTZ resistant
Trichomoniasis
Sexually transmitted infection (STI)

1. Introduction regimens to cure T. vaginalis infection is of serious concern [9,10].

Trichomoniasis is the most common non-viral sexually trans-
mitted disease (STD) in the world caused by the flagellate proto-
zoan Trichomonas vaginalis (T. vaginalis) with highest rate of
incidence, 276 million new cases each year as reported by WHO [1].
Humans are the natural host for the parasite and it can cause
urogenital track infection both in male and female. However, the
infection is curable but may cause severe health consequences in
females such as cervical cancer, infertility, HIV (Human Immuno-
deficiency Virus) acquisition and adverse pregnancy outcomes
leading to premature rupture of placental membranes, premature
labour and low-birth weight infants [2,3]. Trichomoniasis is
generally asymptomatic in men but recent finding of its association
to prostate cancer is alarming [4,5]. Another immediate fret about
trichomoniasis is its association with HIV acquisition and trans-
mission as supported by current research findings [6e8].
The classic treatment for trichomoniasis involves 50 -nitro-
imidazole agents, of which metronidazole (MTZ) is the only effec-
tive approved drugs. There has been continuous increase in the
recognition of MTZ-resistant trichomoniasis and the failure of MTZ
Those erroneous cases are therefore usually treated with increased
doses of the MTZ, which may lead to an increase in the rate of side
effects [11]. Undoubtedly, alternative curative therapies are needed
for Trichomoniasis treatment including protection strategies.
In this review, we will give a brief but comprehensive overview
of the advances in the research on trichomoniasis treatment from
the last 10 years including both synthetic and natural product
research. The aim of this report is to put together anti-Trichomonas
activity results of synthetic compounds along with natural
products.
2. Synthetic products to treat T. vaginalis
Synthetic compound research is always an important tool in
drug discovery. In the last decade to find out an effective MTZ
alternative to cure trichomoniasis, a variety of chemical libraries
have been synthesized and biologically tested for the same. We
have grouped these compounds based on their structural similarity.
2.1. 5-Nitroimidazole derivatives

Research is still going on 5-Nitroimidazoles to find out alternate

* Corresponding author.
** Corresponding author.
derivative of similar class with a hope to revert the MTZ resistance
E-mail addresses: veenu2bala@mlsu.ac.in, veenu2bala@gmail.com (V. Bala), against T. vaginalis and to increase the potency. Upcroft et al. have
yashpal111@gmail.com (Y.S. Chhonker). synthesized a series of thirty 5-nitroimidazole derivatives to be

https://doi.org/10.1016/j.ejmech.2017.11.029
0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.
 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243 233

effective against MTZ resistant T. vaginalis. Three compounds have imidazole acetamide and imidazole sulfonamide analogues. Among
been appeared as fivefold more effective than MTZ against resistant acetamide derivatives four compounds (7e10) showed high
T. vaginalis clinical isolates (B7268, MIC 3.1e10 mM and DUR36, MIC bioactivity (<10 mM) against T. vaginalis and sulfonamide de-
1.6e6.3 mM). Compound 1 was found to be most effective with MIC rivatives resulted into most active compound 11 with IC50 2.93 mM
3.1 mM and 1.6 mM against T. vaginalis B7268 and DUR36, respec- [17] (see Fig. 2).
tively [12]. Anthwal and cogners synthesized novel MTZ-chalcone
hybrids and screened against MTZ susceptible and resistant Tri-
2.2. Benzimidazole derivatives
chomonas. All hybrids were active against both MTZ susceptible
(MIC 1.56e25 mg/mL) and resistant (MIC 3.125e100 mg/mL) strains.
A series of bisbenzimidazole analogs (ten compounds) have
Two compounds (2, 3) have shown superior activity profile (>4
been tested for anti-Trichomonas activity by Korosh and co-
times, MIC 3.125 mg/mL) in comparison to MTZ (MIC 12.5 mg/mL)
workers. Compound 12 was found to be the most potent, about
against MTZ resistant Trichomonas without forfeiting activity to
5.5-fold more active (MIC, 26 mM) than MTZ (MIC, 145 mM) against
susceptible strain (MIC 1.56 mg/mL). These compounds have also
resistant strain. Compound 12 was evaluated for in vivo anti-Tri-
shown safety against HeLa cells and compatibility with vaginal flora
chomonas activity by using subcutaneous mouse model infected
[13].
with the MTZ-resistant isolate 085 at 25 mg kg1 day1 for 4 days
A library of sixty 2-methyl-4/5-nitroimidazole derivatives have
and showed 100% efficacy [18].
been synthesized by D. Mandalapu et al. via nucleophilic ring
A series of nitazoxanideeN-methylbenzimidazole hybrids (13)
opening reaction of epoxide. All the molecules (except two) were
have been synthesized to test their antiprotozoal activity. The IC50
active against both susceptible and resistant strains of T. vaginalis
value of those compounds against T. vaginalis was 0.023
with MICs ranging from 8.55 to 336.70 mM and 28.80e1445.08 mM,
mMe0.0356 mM [19]. 2-(trifluoromethyl)-1H-benzimidazole de-
respectively. The most promising compound 4 (MIC, 8.55 mM
rivatives (14) also possess anti-Trichomonas activity with IC50 values
against susceptible and MIC, 37.10 mM against resistant strain) was
ranging from 0.016 to 0.970 mM concentration [20].
screened for in vivo anti-Trichomonas activity using the mouse ab-
Carboxylic acid derivatives as esters and amides of 1-
scess assay. There was a significant decrease in abscess size after
methylbenzimidazole have been screened for their anti-Trichomo-
treatment with compound 4 in comparison to MTZ treated group
nas activity. Both compound series exhibited superior activity (IC50
[14] (see Fig. 1).
0.0275e0.5117 mM) profile than standard drug MTZ (IC50,
An extensive research has also been carried out by Kumar et al.
1.2260 mM) but ester derivatives (15) were found most active with
to potentiate MTZ scaffold to be effective against resistant
IC50 value 0.0275e0.0686 mM [21].
T. vaginalis. They synthesized a series of MTZ-dithiocarbamates
A series of ten novel hybrids of benzimidazole and pentamidine
hybrids as 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)ethyl-4-
tested for their in vitro antiprotozoal activity including anti-Tri-
substituted piperidine-1-carbodithioates and evaluated them
chomonas potential. 1,5- bis[4-(5-methoxy-1H-benzimidazole-2-yl)
against both MTZ susceptible and resistant T. vaginalis strains. All
phenoxy]pentane (16) was about twice active than standard MTZ
the synthesized 13 compounds showed 1.2e12.1 times more effi-
(IC50, 0.286 mM) with IC50, 0.164 mM [22].
cacy (MIC 24.1e246 mM) against MTZ resistant strain than MTZ
Novel benzimidazole derivatives as 2-{[2-(1H-imidazol-1-yl)
itself (MIC 292 mM). The activity profile of most active compound 5
ethyl]sulfanyl}-1H benzimidazole (17) have been synthesized and
was, MIC 1.68 mM against susceptible and MIC 24.1 mM against
their biological assays against T. vaginalis revealed strong activity
resistant strain [15]. Carboxamide derivatives of nitroimidazole
profile (IC50, 0.0698e0.1780 mM) in comparison to MTZ [23] (see
have also been identified for their anti-Trichomonas activity. The
Fig. 3).
compounds had potent activity against susceptible T. vaginalis, with
EC50 values (EC50 ¼ 0.6e1.4 mM) comparable to MTZ
(EC50 ¼ 0.8 mM). Compound 6 with morpholine substituent was 2.3. Amine derivatives
most active for this activity at EC50, 0.6 mM [16].
Two newer series of imidazole have been synthesized as Zuanazzi et al. synthesized five different diamines and amino
alcohol derivatives and evaluated for anti-Trichomonas activity at

Fig. 1. 5-Nitroinidazole derivatives (1e4)as anti-Trichomonas agents.

234 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243

Fig. 2. 5-Nitroinidazole derivatives (5e11)as anti-Trichomonas agents.

Fig. 3. 5-Nitroinidazole derivatives (12e17)as anti-Trichomonas agents.

five different concentrations (0.1e1.5 mg/mL). Compound 18 among
diamine derivative have displayed comparable anti-Trichomonas
activity at all the tested concentrations against a fresh clinical (TV-
VP60) and a long-term-grown (ATCC 30236) strain to MTZ [24].
N-monoalkylated diamines were synthesized and evaluated for
in vitro activities against T. vaginalis. N-hexadecil-1,4-
butanediamine (19) was found to be the most active compound
against T. vaginalis with MIC, 2.5 mg/mL, twice more active to MTZ
(5.0 mg/mL) [25]. 3,4-dichloroaniline amides also possess anti-
Trichomonas activity as compound 20 has shown 69% inhibition at
100 mM concentration [26] (see Fig. 4).
2.4. Isatin derivatives
bioactivity against G3 strain of T. vaginalis. Compound 21 with
phenyl-substituent on N-1 of b-lactam ring and unsubstituted
isatin ring was found to be the most active showing IC50 of 7.69 mM
along with non-cytotoxic behaviour [27].
They further synthesized mono and bis-uracil isatin conjugates
and evaluated against T. vaginalis at 50 mM. Bis-uracil isatin con-
jugates exhibited better inhibitory profile (>90% inhibition) at
50 mM, compared to mono uracil isatin conjugates. Compound 22
with chloro substituent exhibited best activity profile (IC50 9.79 mg/
mL) [28] (see Fig. 5).
2.5. Already approved marketed drugs tested for anti-Trichomonas
activity

Vipan Kumar and coworkers have synthesized eighteen com- Miltefosine (MLT) is an alkylphosphocholine a membrane-active
pounds as 1H-1,2,3-triazole linked b-lactam-isatin bi-functional synthetic lipid analogue, and was first used for the treatment of
hybrids by copper-catalyzed ‘click chemistry and performed cutaneous metastasis from mammary carcinomas. Based on the
 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243
Fig. 4. Amine derivatives(18e20) as anti-Trichomonas agents.
Fig. 5. Isatin derivatives (21-22) as anti-Trichomonas agents.
previous reports of MLT to possess antiparasite activity, Rocha et al.
investigated the antiproliferative effect of MLT on the viability and
structural organization of T. vaginalis. The IC50 values of MLT were
14.5 and 20 mM for 24 and 48 h incubation periods, respectively. The
cells treated with MLT displayed several ultrastructural alterations;
wrinkled cells, rounded cells and membrane blebbing as observed
with Transmission electron microscopy (TEM) [29] (see Fig. 6).
Proton pump inhibitors (PPIs), omeprazole, lansoprazole, pan-
toprazole and rabeprazole have been extensively used for the
treatment of peptic ulcer, gastroesophageal reflux, and the eradi-
cation of Helicobacter pylori in combination with antibiotics. The
anti-Trichomonas activity of these marketed PPIs have been carried
out and all four tested PPIs have displayed anti-Trichomonas activity
(IC50 ¼ 0.0756 mM-0.1218 mM), in which pantoprazole was thrice
more active (IC50 ¼ 0.0756 mM) than MTZ (IC50 ¼ 0.2360 mM) [30].
Tara A. Shah et al. carried out the mechanistic study and identified
the PPIs (omeprazole, pantoprazole, rabeprazole) as uridine ribo-
hydrolase inhibitors, the enzyme required by the parasite
T. vaginalis to scavenge uracil for its growth [31]. Octenidine
Fig. 6. Approved marketed durgs with anti-Trichomonas potential.
235
dihydrochloride is a well-known cationic surface-active agent & its
mode of action is binding to anionic structures of the cell mem-
brane, further bursting of the membrane. Octenidine dihydro-
chloride and phenoxyethanol combination was found to be highly
effective against T. vaginalis with no difference between MTZ
resistant and susceptible strains. The 50% effective concentration
(EC50) values ranged from 0.68 to 2.11 mg/mL after 30 min of
treatment depending on the protein concentration of the test me-
dium [32]. In another study of approved drugs, antiretroviral pro-
tease inhibitors were assessed in vitro for their anti-Trichomonas
activity against MTZ resistant strain. Kaletra® (a co-formulation of
ritonavir and lopinavir), was found most effective for the above
activity with MIC ranging from 10 to 50 mM [33]. 0.2% concentration
of boric acid also showed significant reduction in the growth rate of
T. vaginalis [34].
2.6. Dual function vaginal microbicides with anti-Trichomonas
potential
Topical vaginal microbicide is one of the women controlled pre-
exposure prophylaxis to prevent HIV/STD (T. vaginalis, Candida
albicans) along with unwanted pregnancy via sperm immobiliza-
tion. Free thiol groups are considered to control the survival of
anaerobic cells like T. vaginalis, C. albicans and spermatozoa
[35e37]. Considering the above dual targeting fact sharma et al.
synthesized a series of carbodithioic acid derivatives of fluoxetine
to provide protection against both pregnancy and Trichomoniasis.
Out of synthesized twenty compounds, seven compounds showed
anti-Trichomonas activity at 7e52 mg/mL concentrations and N-
methyl-[3-phenyl-3-(4-trifluoromethylphenoxy)-propyl]carbodi-
thioic acid S-(2-pyrrolidino-ethyl) ester (23) has shown better
236 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243
activity profile showing all three activities altogether spermicidal
0.05%, anti-Trichomonas 14 mg/mL and antifungal 3.12e25 mg/mL
[38]. They further reported structural hybrid of thiol containing
moieties, i.e. dithiocarbamate and disulfide (24) and evaluated their
action via sulfhydryl (SH) binding against human sperm and
T. vaginalis. Eleven compounds (MIC, 3.12e50.0 mg/mL) have
demonstrated considerable anti-Trichomonas activity against
resistant strain than MTZ (MIC, 50.0 mg/mL) [39].
Sharma et al. group also designed Pyrrolidinium pyrrolidine-1-
carbodithioate, (PPC, 25) and its derivatives for prophylactic
contraception. Its activity profile against human sperm (MEC,
145 mM) and T. vaginalis against susceptible (MIC 5.25 mM) and
resistant strains (MIC 13.50 mM) was considerably higher than
standard, Nonoxynol-9 (N-9, MEC 243 mM) and MTZ (MIC 13.64 mM
for susceptible strain and MIC 358 mM for resistant strain) [40].
Inspiring from the PPC results they have synthesized fifteen new
compounds i.e secondary amine salts of dialkyldithiocarbamic acid
(26) and identified eleven compounds with potent to moderate
(MIC 11.94e332.13 mM) anti-Trichomonas activity. All the com-
pounds exhibited greater safety toward HeLa cells and much better
compatibility with Lactobacillus. [41] They further extended the
study by reporting twenty-nine Ammonium salts of carbamodi-
thioic acid. Eleven compounds have shown anti-Trichomonas ac-
tivity comparable to MTZ against susceptible strains
(MIC ¼ 3.25 mg/L) and much more effective for resistant T. vaginalis
(MICNEW ¼ 6.25e25.0 mg/L vs. MICMTZ ¼ 50.0 mg/L). Compound 27
had the best activity profile against susceptible (MIC, 1.56 mg/L)
and resistant Trichomonas (MIC, 7.8 mg/L) along with spermicidal
activity (MEC, 61.5 mg/L). Compound 27 was found to be active
in vivo as displayed by mouse subcutaneous abscess assay [42] (see
Fig. 7).
In continuation of research on potent vaginal microbicides the
group also reported 3-(azol-1-yl)phenylpropanes (28) as micro-
bicidal spermicides, and among twenty five synthesized com-
pounds ten have shown complete sperm immobilization at 1%
concentration. Twelve compounds showed potent microbicidal
activity at 12.5e50 mg/mL against T. vaginalis. [43] Twenty-seven
Fig. 7. Dual function vaginal microbides with anti-Trichomonas potential (23e29).
imidazole derivatives as 2-(2-methyl-5-nitro-1H-imidazol-1-yl)
ethanol (29) have been synthesized for the above purpose. All the
compounds were active against T. vaginalis at MIC ranging from 1.0
to 111.0 mM whereas the standard drug MTZ was active at 11.7 mM
[44].
Bala et al. reported carbamodithioates derivatives as non-
surfactant dually active vaginal microbicidal spermicides to
interact with SH groups. The most promising compound was 2
(pyrrolidin-1-yl)ethyl piperidin-1-ylcarbamodithioate (30) with
spermicidal (MEC 0.36 mM), anti-Trichomonas activity against both
MTZ susceptible (MIC, 0.056 mM) and MTZ resistant strains (MIC,
0.228 mM) [45]. They further thought to incorporate anti-HIV po-
tential in the compounds along with above activities as sexual
mode is the most dominant mode of HIV transmission [46]. For that
purpose, they hybridize dithiocarbamate moiety with thiourea to
target T. vaginalis, sperm and HIV altogether. The study resulted in
twelve dually active compounds of which the most promising
compound was octyl 4-(benzoylcarbamothioyl) piperazine-1-
carbodithioate (31) as it showed anti-Trichomonas (MIC, 15.56 mg/
mL), spermicidal (MEC, 0.025%) activity and RT inhibition (% inhi-
bition, 41.29) [47]. In order to enhance the RT inhibition potential,
they synthesized a novel series of N-Alkyl/aryl-4-(3-substituted-3-
phenylpropyl)piperazine-1-carbothioamide derivatives. The most
promising compound, N-butyl-4-(3-oxo-3-phenylpropyl) piper-
azin-1-carbothioamide (32) exhibited better activity profile than N-
9 as it showed RT inhibition (72.30%), anti-Trichomonas (MIC,
46.72 mM against MTZ susceptible and MIC, 187.68 mM against
resistant strain) and spermicidal (MEC, 0.01%) activity. Among
synthesized fifteen compounds, nine were more active (MIC,
118.37e260.96 mM) against MTZ resistant Trichomonas strain in
comparison to MTZ (MIC, 292.80 mM) [48].
Another group of pandey et al. have synthesized 3-(1-alkyl/
aminoalkyl-3-vinyl-piperidin-4-yl)-1-(quinolin-4-yl)-propan-1-
ones and their 2-methylene derivatives as potential microbicidal
spermicide. They primarily checked spermicidal activity and for
active compounds (MEC 0.5%) anti-Trichomonas assay was carried
out. Compound 33 spermicidal MEC, 0.01% and anti-Trichomonas
 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243 237

(MICsusceptible ¼ 1.5 mg/mL, MICresistant ¼ 3.125 mg/mL) was found as

a better microbicidal spermicide than N-9 (spermicidal MEC, 0.02%)
and MTZ (MICsusceptible ¼ 2.0 mg/mL, MICresistant ¼ 62.5 mg/mL) [49]
(see Fig. 8).

2.7. Miscellaneous agents

Pan et al. studied the antimicrobial activities of three synthetic

peptides derived from epinecidin-1. These compounds were active
against MTZ-resistant T. vaginalis (MIC 12.5e200 mg/mL). TEM and
scanning electron microscopy (SEM) examinations of T. vaginalis
treated with these peptides showed severe swelling and breakage
of the outer membrane, and efflux of the intracellular inclusion
[50]. Benchimol et al. has carried out anti-Trichomonas activity
study of 3-(biphenyl-4-yl)-3-hydoxyquinuclidine (BPQ-OH, 34).
BPQ-OH inhibit in vitro proliferation of T. vaginalis at IC50, 46 mM
[51].
Betulinic acid derivatives exhibited remarkable anti-Trichomo-
nas activity against resistant strain ATCC 30236 with reduced
parasite viability by 100% [52].
During the ongoing efforts of Berzel and group to target parasitic
protozoan infections through synthesis of novel nitroheterocycles,
two new indazole derivatives have been synthesized and tested for
anti-Trichomonas activity. Compound 35, 3-(3-hydroxypropoxy)
indazole derivative had an appropriate activity with IC50 values
7.25 mM and 9.11 mM against MTZ susceptible and resistant strains,
respectively [53]. Sharma et al. group have reported chalconyl
blended triazole allied organosilatranes as giardicidal and tricho-
monacidal agents. All the synthesized compounds displayed sig-
nificant activity against T. vaginalis with IC50 values ranging from
18.24 to 101.26 mM [54]. 2-acylamino-5-nitro-1,3-thiazole de-
rivatives have been tested against neglected protozoan parasites
including T. vaginalis. Compound 36 i.e. ethyloxamate derivative
(IC50 ¼ 10 nM) was 29-times more active than MTZ (IC50 ¼ 290 nM)
[55] (see Fig. 9).
Benzologues of Nitazoxanide and Tizoxanide have been
screened for their anti-protozoal activity profile and benzologue of
Nitazoxanide, 37 was found to be broad spectrum antiprotozoal
agent including activity against T. vaginalis, IC50 ¼ 842 nM [56]. 4-
amino-7-chloroquinoline and ferrocenylimine derivatives have also
shown anti-Trichomonas activity with 34.9e61.5% inhibition at
tested 10 mM conc [57].
New polynuclear organometallic Ru(II), Rh(III) and Ir(III) pyridyl
ester complexes tested for their anti-Trichomonas activity, the
Fig. 9. Miscellaneous agents (34e37) as anti-Trichomonas agent.
tripyridyl ester iridium complex exhibited about 95% trophozoite
inhibition at tested 50 mM conc [58].
A study was carried out to investigate N-chlorotaurine (NCT)
and its combination with ammonium chloride (NH4Cl) against
T. vaginalis. The activity of NCT was enhanced by NH4Cl against both
MTZ susceptible and resistant strains. Only one-third of the NCT
concentration was needed to achieve 100% inhibition when NH4Cl
was added, i.e. 5.5 mM (0.1%) NCT plus 19 mM (0.1%) NH4Cl [59].
3. Natural products to treat T. vaginalis
Natural products are important source of new drugs and also
explore diverse lead structures, further used as templates for the
new drug development by pharmaceutical industry. In recent years,
the inclination of medicinal chemist has been increased towards
natural plants for drug discovery mainly due to lack of side effects.
It should also be noted that out of 15 anti-parasitic medications
approved by health authorities between 1981 and 2010, >50% are
natural products or derivatives [60]. Natural plant products
research for anti-Trichomonas activity has also been increased in the
past decade as depicted in Tables 1 and 2. The overall natural
product research can be further categorized into two types, in first
type of study crude plant extracts have been investigated for anti-
Trichomonas activity (Table 1) while in second type of study the
extracts were chemically characterized and their activity profile has
been established (Table 2).

Fig. 8. Dual function vaginal microbides with anti-Trichomonas potential (30e33).

238 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243
Table 1
Natural plant products composition showing anti-Trichomonas potential.
Plant source Composition
Dried bean seed coats Acidified water (AW) and Acetic acid (AA) extracts
(Lectins) of Phaseolus vulgaris
Perla black bean
(Fabaceae)
Leaves of Voacanga globose (Apocynaceae) Ethanolic extract
Leaves of Cussonia species L (Araliaceae) Methanolic extract
Leaves of Eucalyptus camaldulensis (Myrtaceae) Ethyl acetate extract
Seeds & oil of Nigella sativa (Ranunculaceae) Alcoholic extract
Roots of Polygala decumbens (Polygalaceae) aqueous extracts
Leaves of Campomanesia xanthocarpa (Myrtaceae) Aqueous extract
Seeds of Persea americana (Lauraceae) Chloroform extract (CE) & Ethanol extract (EE)
Pistacia lentiscus Gum from stem bark
(Anacardiaceae)
Lara diaz & co-workers have investigated the microbiological
and toxicological effects of Perla black bean (Phaseolus vulgaris L.)
extracts on the growth and culture of selected pathogenic micro-
organisms. Acidified water (AW) and Acetic acid (AA) extracts have
shown remarkable anti-Trichomonas activity profile,
MICAW ¼ 176.8 mg/mL and MICAA ¼ 378.3 mg/mL [61]. Ethanolic
extract of Vocanga globose leaves, enriched with alkaloids, flavo-
noids, tannins & phenolic compounds have shown comparable
anti-Trichomonas activity to MTZ [62]. Thirteen Cussonia species
were tested against pathogens associated with sexually transmitted
infections (Neisseria gonorrhoeae and T. vaginalis) by Villiers et al.
Methanolic extract of Cussonia sp. leaves have displayed anti-Tri-
chomonas activity at MIC 0.8e1.3 mg/mL [63]. Five different ex-
tracts including total extract, diethyl ether, chloroform, ethyl
acetate, and water fractions were prepared from leaves of Euca-
lyptus camaldulensis and all these extracts were tested for their
anti-Trichomonas potential. Ethyl acetate extract have displayed
maximum activity profile with 100% inhibition at 12.5 mg/mL [64].
Aminou et al. investigated the therapeutic potential of Nigella sativa
alcoholic extract and oil, as well as P. vulgaris (kidney bean) lectin
and their activity on the ultrastructure of T. vaginalis at a conc. of
500 mg/mL in comparison to MTZ. TEM studies showed severe cell
damage with cytoplasmic and nuclear destruction after N. sativa oil
and P. vulgaris lectin treatment [65].
Tasca et al. have evaluated anti-Trichomonas activity of 44
aqueous extracts obtained from 23 Caatinga plants (found in the
Brazilian semi-arid region) against two ATCC isolates and four fresh
clinical isolates. Among all tested species only Polygala decumbens
root extract significantly reduced the trophozoite viability with MIC
value 1.56 mg/mL against MTZ resistant strain [66]. In another
study Tasca et al. evaluated the anti-T. vaginalis activity of 10 me-
dicinal plants widely used by Mby'a-Guarani indigenous group.
Among the aqueous extracts tested, Campomanesia xanthocarpa
showed the highest activity with MIC value of 4.0 mg/mL [67].
CHCl3 and EtOH extracts from Persea americana seeds displayed
remarkable activity against T. vaginalis with IC50 values 0.524 g/mL
and 0.533 g/mL, respectively [68]. Eldin & Badawy investigated the
in vitro effects of Pistacia lentiscus mastic and Ocimum basilicum oil
on T. vaginalis trophozoites. The results showed that both plants
caused growth inhibition of T. vaginalis trophozoites and morpho-
logical changes were also reported by (TEM). The MIC of P. lentiscus
mastic was 10 mg/mL and of O. basilicum oil was 20 mg/mL after
48 h incubation [69].
Table 2 depicts study of isolated/identified compounds to be
effective against T. vaginalis. Monocrotaline alkaloid obtained from
Crotalaria retusa seeds was identified to possess anti-Trichomonas
potential by Giordani et al. Monocrotaline showed 74% Trichomonas
Anti-Trichomonas Activity Ref.
MICAW ¼ 176.8 mg/mL [61]
MICAA ¼ 378.3 mg/mL
Comparable to MTZ [62]
MIC ¼ 0.8e1.3 mg/mL [63]
MIC ¼ 12.5 mg/mL [64]
MIC ¼ 500 mg/mL [65]
MIC ¼ 1.56 mg/mL against TV resistant strain LACM-2 [66]
MIC ¼ 4 mg/mL [67]
IC50 CE ¼ 0.524 mg/mL [68]
IC50 EE ¼ 0.533 mg/mL
MIC ¼ 10 mg/mL [69]
inhibition. at 1 mg/mL, in addition, neither cytotoxicity against
vaginal epithelial cells nor hemolytic activity were observed. They
have also synthesized its derivative as azido-retronecine and it was
more active than monocrotaline killing 85% of the parasites at 1 mg/
mL [70]. Friedman et al. investigated the inhibitory effects of the
commercial tetrasaccharide tomato glycoalkaloid tomatine and the
aglycone tomatidine on T. vaginalis strain G3. Screening data
showed that tomatine completely inhibited T. vaginalis strain G3 at
100 mM [71].
Tasca et al. evaluated the anti-trichomonads activities of seven
fractions from northwest endemic plant Manilkara rufula. Flavo-
noids and condensed tannins identified from M30 and M100 frac-
tions have shown high anti-Trichomonas activity. M30 and M100
fractions were employed to determine the MIC using a range of
concentrations from 2.0 to 0.0156 mg/mL. None of the concentra-
tions at this range abolish the 100% viability of T. vaginalis [72].
In another study, Tasca et al. demonstrated anti-Trichomonas
potential of saponins from Quillaja, Passiflora, and Ilex species.
Among them Passiflora alata and Quillaja saponaria saponins
exhibited the best anti-T. vaginalis activity (MIC 0.025%). Lactate
dehydrogenase (LDH) assay results indicated the mechanism of
anti-Trichomonas activity probably by membrane damage [73].
A study was done to determine the efficacy of curcumin, a
derivate of Curcuma longa, on T. vaginalis. After 24 h of incubation,
the EC50 (effective concentration) ranged from 73.0 to 105.8 mg/mL
against three tested strains (ATCC 30001, ATCC 30236 and ATCC
50138) [74].
Consolaria et al. tested water-ethanol (WE) and butanolic (BE)
extract from S. saponaria, as well as purified sample of saponins (SP)
for spermicidal and anti-Trichomonas activity. The compounds were
effective against clinical strain of T. vaginalis (MIC ¼ 0.156 mg/mL
for WE and BE, and 0.078 mg/mL for SP) and also against ATCC
strain (MIC ¼ 0.312, 0.156 and 0.078 mg/mL for WE, BE and SP,
respectively) [75]. Almeida & group carried out the anti-T. vaginalis
activity of Lycorine and its semisynthetic ester derivatives. Lycorine
is amaryllidaceae alkaloid obtained from bulbs of Hippeastrum
santacatarina. The study resulted into interesting results as
monoester derivative of lycorine, 2-O-lauroyllycorine displayed
100% Trichomonas inhibition at 250 mM [76].
Sun et al. described the first report on the activity and
morphological changes of Amomum tsao-ko essential oil and gera-
niol against T. vaginalis. IC50 of A. tsao-ko essential oil was 22.49 mg/
mL for T. vaginalis isolate Tv1, and 44.97 mg/ml for isolate Tv2 while
for geraniol were 342.96 mg/mL and 171.48 mg/mL, respectively.
Morphological changes of T. vaginalis were observed by TEM and
include damage of nuclear membrane, accumulation of chromatin,
appearance of numerous vacuoles in the cytoplasm, dilation of
 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243 239

Table 2
Isolated/identified compounds from natural plants showing anti-Trichomonas activity.

Plant Source Isolated/identified compounds (Anti-Trichomonas Activity) Ref.

Seeds of Crotalaria retusa (Fabaceae) [70]

Leaves of Solanum lycopersicum (Solanaceae) [71]

Leaves of Manilkara rufula (Sapotaceae) [72]

Leaves of Passiflora alata [73]

(Passifloraceae)

Leaves of Ilex paraguariensis (Aquifoliaceae) [73]

Leaves of Quillaja saponaria [73]

(Quillajaceae)

Rhizome of Curcuma longa [74]

(Zingiberaceae)

Dry pericarps of the fruits of Sapindus saponaria (Sapindaceae) [75]

Bulbs of Hippeastrum santacatarina [76]

(Amaryllidaceae)

Fruit of Amomum tsao-ko [77]

(Zingiberaceae)

Flower of Rheum ribes L. (Polygonaceae) [78]

Ocimum basilicum [69]

(Lamiaceae)

Leaf of Arbutus unedo [79]

(Ericaceae)

(continued on next page)

240 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243
Table 2 (continued )
Plant Source
Fruits of Solanum torvum (Solanaceae)
Seeds of Dalbergia
Cochinchinensis
(Fabaceae)
Flower of Plumeria obtuse
(Apocynaceae)
Leaves of Ligustrum japonicum
(Oleaceae)
Leaves of Gonocaryum subrostratum
(Icacinaceae)
flowers & buds of Hypericum polyanthemum
(Hypericaceae)
rough endoplasmic reticulum [77].
The essential oil from Rheum ribes L. flower growing wild in Iran
was analyzed by GC/MS and a total number of 19 compounds have
been identified from different plant part extract. The major con-
stituents of R. ribes flower essential oil were palmitic acid (27.08%),
n-eicosane (9.9%), n-tetracosane (7.34%), linoleic acid (6.56%), and
ethyllinoleate (4.76%).The parasites were treated with different
extract and fractions of the flower, stem, and leave of the plant in
order to ascertain anti-Trichomonas potential. Anti-Trichomonas
activity profile (MIC, 0.5-1.0 mg/mL) suggests its further develop-
ment for human use [78].
In a study, ethanolic, water, hexane and ethyl acetate extracts of
Arbutus unedo leaves were evaluated against T.vaginalis and the
ethyl acetate extract was found to be effective at the concentration
of 500 mg/mL (Growth inhibition rate (GI): 100%) [79]. A study was
carried out to investigate anti-Trichomonas effect of b-glycosides
and several aglycones purified from Thai plants. The MIC for all b-
glycosides against T. vaginalis was in a range of 6.25e12.5 mM [80].
Cargnin and group assessed the anti-T. vaginalis activity of
Hypericum polyanthemum extract obtained by supercritical fluid
extraction (50  C, 150 bar) and the isolated chemical compounds
from this extract uliginosin B, a phloroglucinol derivative, and three
benzopyrans: 6-isobutyryl-5,7-dimethoxy- 2,2-
dimethylbenzopyran (HP1), 7-hydroxy-6-isobutyryl-5-methoxy-
2,2-dimethyl-benzopyran (HP2) and 5-hydroxy-6-isobutyryl-7-
methoxy-2,2-dimethylbenzopyran (HP3). HP1 demonstrated the
best selectivity against both MTZ-resistant and susceptible strains
Isolated/identified compounds (Anti-Trichomonas Activity) Ref.
[80]
[80]
[80]
[80]
[80]
[81]
[81].
Jasmonates are a group of small lipids produced in plants and
selectively cytotoxic against cancer cells. Methyl jasmonate (MJ) is a
naturally occurring jasmonate showing mitochondriotoxic effects.
Flesher et. Al. studied the anti-Trichomonas effect of synthetically
available MJ towards a MTZ-resistant strain of T. vaginalis (ATCC
50143), and found to exhibit mitochondria-independent cytotox-
icity against T. vaginalis [82].
In order to develop a natural microbicidal contraceptive, anti-
Trichomonas potential of Sapindus saponins has been evaluated by
Tiwari et al. These Sapindus saponins were a mixture of six
sapindosides, with sapindoside B as one of the major constituents,
isolated by n-butanol extraction of the ethanolic extract of fruit
pericarp of Sapindus mukorossi Gaerth (Reetha or soap nut). The
anti-Trichomonas activity of this sapindus saponin mixture was
found to be 10-fold lower (0.005%) than its minimal effective
spermicidal concentration (0.05%) [83]. In another study to target
sperm and T. vaginalis altogether, a synthetic spermicide (DSE-37)
was combined with a sapindus saponin, and were evaluated in vivo
against human sperm & T. vaginalis. A 0.003% drug combination
containing 0.0015%, each of DSE-37 and sapindus saponin irre-
versibly immobilized 100% human sperm in 30 s and 100%
T. vaginalis in 24 h, without disrupting human cervical (HeLa) cells
in 24e48 h [84].
A clinical trial study was carried out to investigate anti-Tricho-
monas potential of Commiphora molmol by Nahda University Egypt.
In that study, 33 MTZ-resistant T. vaginalis females have given a
 V. Bala, Y.S. Chhonker / European Journal of Medicinal Chemistry 143 (2018) 232e243
combined course of MTZ and tinidazole. Further, those remain still
resistant to the treatment were given oleo-resin extract of
C. molmol orally for 6e8 successive days The cure rate for C. molmol
was found to be 84.6%.[85].
Anti-Trichomonas activity of marine-associated fungi found in
the South Brazilian Coast has been evaluated by Tiana Tasca et al.
Two filtrate samples from Hypocrea lixii F02 and Penicillium cit-
rinum F40 showed significant anti-Trichomonas activity against
MTZ-resistant isolate at 2.5 mg/mL[86].
4. Conclusion
We have briefly described various synthetic and natural product
research employed for the development of diverse anti-Trichomo-
nas agents in the last one decade. Nitroimidazoles, MTZ is the most
prescribed and effective drug against T. vaginalis. But the develop-
ment of resistance against T. vaginalis across the globe has made the
researchers to develop some alternatives to MTZ. Our study has
introduced the variety of synthetic chemical libraries and medicinal
plants altogether showing promising anti-Trichomonas activity. The
present review has suggested that several synthetic and natural
leads could be further developed as potential drug candidates to
cure T. vaginalis. Further, it is presumed that the information
compiled in this review article will not only update scientists with
recent anti-Trichomonas research findings but also encourage them
to further explore promising novel agents to combat T. vaginalis
infection.
Conflicts of interest
Authors confirm that this article content has no conflicts of
interest.
Acknowledgement
This study was partially supported by University grant com-
mission-Start up grant F.30e41/2014 (BSR).
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