Hybrid molecules of carvacrol and benzoyl urea/thiourea with potential applications in agriculture and medicine

Article abstract of DOI:10.1016/j.bmcl.2012.07.017

Benzoyl phenyl urea, a class of insect growth regulator's acts by inhibiting chitin synthesis. Carvacrol, a naturally occurring monoterpenoid is an effective antifungal agent. We have structurally modified carvacrol (2-methyl-5-[1-methylethyl] phenol) by introducing benzoylphenyl urea linkage. Two series of benzoylcarvacryl thiourea (BCTU, 4a-f) and benzoylcarvacryl urea (BCU, 5a-f) derivatives were prepared and characterized by elemental analysis, IR, ¹H and ¹³C NMR and Mass spectroscopy. Derivatives 4b, 4d, 4e, 4f and 5d, 5f showed comparable insecticidal activity with the standard BPU lufenuron against Dysdercus koenigii. BCTU derivatives 4c, 4e and BCU 5c showed good antifungal activity against phytopathogenic fungi viz. Magnaporthe grisae, Fusarium oxysporum, Dreschlera oryzae; food spoilage yeasts viz. Debaromyces hansenii, Pichia membranifaciens; and human pathogens viz. Candida albicans and Cryptococcus neoformans. Compounds 5d, 5e and 5f showed potent activity against human pathogens. Moderate and selective activity was observed for other compounds. All the synthesized compounds were non-haemolytic. These compounds have potential application in agriculture and medicine.

Full text of DOI:10.1016/j.bmcl.2012.07.017

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5550–5554
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Hybrid molecules of carvacrol and benzoyl urea/thiourea with potential
applications in agriculture and medicine
Umesh D. Pete a, Chetan M. Zade a, Jitendra D. Bhosale a, Santosh G. Tupe b, , Preeti M. Chaudhary b,
⇑
Amol G. Dikundwar c, Ratnamala S. Bendre a,
⇑
a Department of Pesticides and Agrochemicals, School of Chemical Sciences, North Maharashtra University, Jalgaon 425001, Maharashtra, India
b Biochemical Sciences Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India
c Solid State and Structural Chemistry Unit (SSCU), Indian Institute of Science, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzoyl phenyl urea, a class of insect growth regulator’s acts by inhibiting chitin synthesis. Carvacrol, a
naturally occurring monoterpenoid is an effective antifungal agent. We have structurally modified carva-
crol (2-methyl-5-[1-methylethyl] phenol) by introducing benzoylphenyl urea linkage. Two series of ben-
zoylcarvacryl thiourea (BCTU, 4a–f) and benzoylcarvacryl urea (BCU, 5a–f) derivatives were prepared and
characterized by elemental analysis, IR, 1H and 13C NMR and Mass spectroscopy. Derivatives 4b, 4d, 4e, 4f
and 5d, 5f showed comparable insecticidal activity with the standard BPU lufenuron against Dysdercus
koenigii. BCTU derivatives 4c, 4e and BCU 5c showed good antifungal activity against phytopathogenic
fungi viz. Magnaporthe grisae, Fusarium oxysporum, Dreschlera oryzae; food spoilage yeasts viz. Debaromy-
ces hansenii, Pichia membranifaciens; and human pathogens viz. Candida albicans and Cryptococcus neofor-
mans. Compounds 5d, 5e and 5f showed potent activity against human pathogens. Moderate and
selective activity was observed for other compounds. All the synthesized compounds were non-haemo-
lytic. These compounds have potential application in agriculture and medicine.
Received 9 April 2012
Revised 4 July 2012
Accepted 6 July 2012
Available online 14 July 2012
Keywords:
Benzoyl phenyl urea
Benzoyl carvacryl urea
Insect growth regulators
Crop protection agents
Antifungal agents
Ó 2012 Elsevier Ltd. All rights reserved.
Hybrid molecules with dual mode of action are an emerging
novel strategy being employed for the generation of new drug can-
didates for various human diseases.1 In present study, the strategy
has been used for the generation of new and more effective agro-
chemicals with insecticidal and antifungal properties.
Accordingly, a known antifungal monoterpenoid carvacrol was
coupled with benzoyl urea or thiourea moiety present in commer-
cially used benzoylphenyl urea (BPU) class insecticide for the syn-
thesis of hybrid molecules and their synthesis, insecticidal and
antifungal activity is discussed.
Benzoylphenyl urea (BPU) is one such class of IGR compounds
which mainly inhibits chitin synthesis and thus interferes with
the formation of insect cuticle.3 Lufenuron, diflubenzuron, pen-
fluzuron, novaluron, flufenoxuron, teflubenzuron, chlorfuazuron,
hexaflumuron are few examples of BPU compounds currently in
use for the control of a wide range of leaf-eating insects and their
larvae in vegetables, fruits and mushrooms (Fig. 1).4 BPU com-
pounds bind to the sulphonylurea receptors (SUR), a group of
ABC-transporters and inhibit the exocytotic movement of the
Insect pests and plant pathogenic fungi are major causes for
crop losses. Many synthetic organic compounds are in use for their
control; however, these traditional pesticides have drawbacks such
as resistance development, unwanted side-effects, persistence in
the environment, toxicity, etc. Insect Growth Regulators (IGRs)
are receiving more practical attention to provide for safer foods
and cleaner environment.2 IGRs inhibit different developmental
stages in the lifecycle of an insect by specific action such as inhibi-
tion of chitin biosynthesis, metamorphosis or breeding.
F
F
Cl
H
N
H
N
H
N
H
N
Cl
F
F
F
F
F
F
F
F
F
F
O
O
F
O
O
F
O
O
F
F
H
Cl
H
Cl
Novaluron
Lufenuron
F
H
N
H
F
N
H
H
N
N
F
O
O
F
F
O
O
F
Cl
F
⇑
Corresponding authors. Tel.: +91 020 25902708; fax: +91 020 25902648
Diflubenzuron
(S.G.T.); tel.: +91 257 2257435; fax: +91 257 2258403 (R.S.B.).
E-mail addresses: sgtupe@yahoo.co.in (S.G. Tupe), bendrers@rediffmail.com (R.S.
Bendre).
Penfluzuron
Figure 1. Representative benzoylphenyl urea insect growth regulators.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.017

U. D. Pete et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5550–5554
5551
vesicles, depolarizes the vesicle membrane through inhibition of K+
HO
HO
channel, which leads to inhibition of N-acetylglucosamine deposi-
tion and subsequent chitin synthesis in the cuticle.5 Chitin is also
an important constituent of fungal cell wall; however, BPU com-
pounds do not affect chitin synthesis in fungi and have been shown
to be ineffective in vivo and in vitro for the control of fungal
pathogens.6,7
O
O
S
O
DMF, Acetic Acid
H2O2
N
H
N
H
N
H
N
H
R
R
(4 a-f)
(5 a-f)
Where, R: 5a = H, 5b = 2-Cl, 5c = 4-Cl, 5d = 2-F, 5e = 4-F, 5f = 2,6-F
Carvacrol (2-methyl-5-[1-methylethyl] phenol),
a phenolic
Scheme 2. Synthesis of benzoylcarvacryl urea derivatives.
monoterpenoid is a constituent of essential oils produced by
numerous aromatic plants and spices such as black cumin (Nigella
sativa L.), marjoram (Origanum majorana L.), oregano (Origanum
vulgare L.) summer savory (Satureja hortensis L.) and thyme (Thymus
vulgaris L.).8–10 The antifungal activity of carvacrol has been demon-
strated against many phytopathogens11,12 and human pathogenic
fungi.13 It causes cytoplasmic membrane damage through lesion
formation and lowering of ergesterol content.14 Rao et al. have sug-
gested calcium burst and inhibition of TOR pathway as a mode of ac-
tion for Carvacrol.15 It is also insecticidal (less effective than BPU)
and has been proved effective against different insect pests like
Thecodiplosis japonensis, Aphis craccivora, and Leucania separata.16,17
For development of better crop protection agents we envisaged
hybrid molecules of carvacrol and benzoylphenyl ureas which will
have dual (insecticidal and antifungal) biological activity. For this,
4-nitroso carvacrol and 4-amino carvacrol were synthesized
according to previously reported procedures.18,19 Using these
derivatives, two series of compounds benzoylcarvacryl thiourea’s
(BCTU, 4a–f)20 and benzoylcarvacryl urea’s (BCU, 5a–f)21 were syn-
thesized (Schemes 1 and 2).
protons of carvacrol ring appeared separately as two singlets at d
6.69 and 7.30. The two equivalent aromatic protons at the meta po-
sition appeared as triplet at d 7.59 and two protons at orthro posi-
tion appeared as doublets at d 7.99. A para position proton
appeared separately as triplet at d 7.50. The hydroxyl proton ap-
peared as singlet at d 9.13 and the remaining two protons attached
to nitrogen atom were appeared as singlet at d 10.36 and d 10.93,
respectively. The % of C: 69.21, H: 6.45 and N: 8.97 were well in
agreement with the calculated values. LC–MS spectrum exhibited
the characteristic peak at 313.20 for [M+H]+ ion clearly matching
with its molecular weight 312.45. To get single crystal, acetone
solution of 4c was subjected to slow evaporation. The molecular
structure of 4c, that is, 4Cl–BCTU was unambiguously confirmed
by X-ray crystallography (Fig. 2). CCDC-805770 contains the sup-
plementary crystallographic data for this compound. The data
can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
All the newly synthesized BCU and BCTU derivatives were
screened for insect growth regulatory (IGR) activity against red
cotton bug, Dysdercus koenigii. Simplicity of rearing in the labora-
tory and sensitivity to morphogenic compounds makes D. koenigii,
the insect of choice for the investigation. The test compounds were
dissolved in acetone (1 mg/ml). The required volume of the test
solutions were then topically applied with the help of microlitre
syringe to the dorsal abdominal region of same aged 5th instar
nymphs. The concentrations of the compounds tested were 10,
All compounds were obtained as pure solids. Characterization of
a representative compound from both BCTU22 and BCU23 series is
discussed. The 1H NMR spectrum of compound 4a (BCTU) dis-
played a doublet at d 1.22, integrating for six protons which was
due to –CH group attached to it. A singlet at d 2.24, integrating
for three protons was due to methyl group on carvacrol ring. A pro-
ton at CH adjacent to two methyl groups appeared as septet at d
3.05. Also, the two aromatic protons of carvacrol ring appeared
separately as two singlets at d 6.67 and 7.27. The two aromatic
equivalent protons appeared as triplet at d 7.53. A proton at para
position appeared separately as triplet at d 7.66. Two ortho aro-
matic protons appeared as doublets at d 7.97. The hydroxyl proton
appeared as singlet at d 9.34. The remaining two protons attached
to nitrogen atom appeared as singlets at d 11.49 and d 12.11
respectively. The % of C: 65.83, H: 6.14 and N: 8.53 were well in
agreement with the calculated values. LC–MS spectrum exhibited
characteristic peak at 329 for [M+H]+ ion clearly matching with
its molecular weight 328.44.
15, 20, 30, 40 and 50 lg/nymph. The treated nymphs were placed
back in the jars after the acetone had evaporated. At least three
replicates (10 insects per replicate) were used for each dose of a
compound. A parallel control group of nymphs treated only with
acetone was set up. The bioactivities of test compounds were
determined by its effects on mortality (toxic/insecticidal effect),
moulting and growth (growth inhibiting/regulating activity).24
Based on the % mortality data, LD50 values (lethal dose lg/nymph)
were calculated using statistical computer program (Indostat
Services, Hyderabad).
The 1H NMR spectrum of compound 5a (BCU) displayed a dou-
blet at d 1.13, integrating for six protons which was due to –CH
group attached to it. A singlet at d 2.46, for six protons was of
two methyl groups on carvacrol ring. A proton adjacent to two
methyl groups appeared as multiplate at d 3.35. Also, the two
The LD50 of BCTU derivatives for 5th instar nymphs were found
to be in the range 11.3–23.6
derivatives the LD50 range was 9.5–21.5
l
g/nymph, whereas for BCU
g/nymph (Table 1). All
l
HO
HO
HO
Ethanol
H2O
NO
HO
NH2
NH3, H2S
HCl, NaNO2
O
(1)
(2)
(3)
Cl
HO
O
S
R
N
H
N
H
NH2
Acetone, NH4SCN
R
(3)
(4a-f)
Where, R: 5a = H, 5b = 2-Cl, 5c = 4-Cl, 5d = 2-F, 5e = 4-F, 5f = 2,6-F
Figure 2. Molecular structure of 4Cl–BCTU (ORTEP diagram drawn at 30% ellipsoi-
Scheme 1. Synthesis of benzoylcarvacryl thiourea derivatives.
dal probability).

5552
U. D. Pete et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5550–5554
Table 1
Insecticidal activity of BCTU and BCU derivatives against Dysdercus koenigii
Compound
Chi Square value (v2
)
Regression equation
LD50
Fiducial limit
Min
Max
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
Lufenuron
Carvacrol
2.72
3.55
1.91
2.73
2.73
7.32
3.33
5.45
3.49
0.75
5.85
1.37
1.90
5.88
0.345 + 3.389x
3.136 + 1.675x
2.458 + 1.928x
3.511 + 1.354x
3.510 + 1.354x
3.347 + 1.569x
2.090 + 2.186x
2.518 + 2.046x
2.497 + 1.996x
3.339 + 1.469x
2.601 + 2.045x
3.898 + 1.269x
3.507 + 1.566x
2.701 + 1.510x
23.6
13.0
20.8
12.6
12.6
11.3
21.5
16.4
18.0
12.5
14.9
09.5
09.0
33.3
21.7
10.9
18.0
10.2
10.2
09.4
18.8
14.3
15.7
10.3
13.0
07.2
07.5
26.7
25.7
15.3
24.0
15.5
15.5
13.7
24.4
18.7
20.7
15.1
17.1
12.6
10.7
41.4
Acetone at highest concentration mortality was <15%
chi-square values were not significant (
of regression lines. The percentage of abnormal adults was found
to be increased with increase in the treatment dose. High doses be-
tween 20 and 50 lg/nymph showed deformities such as smaller
a
= 0.05) indicating good fit
compounds are given in Table 2 as Minimum Inhibitory Concentra-
tion (MIC) values. MIC was defined as the lowest concentration
exhibiting >90% inhibition of visible growth compared to growth
of the control.
body size, crumpled wings and deformed legs (abnormal adults)
in some of the emerging adult population. 2,6-Fluoro derivatives
(5f) showed the highest activity amongst respective series. Fluoro
substitutes BCTU, BCU compounds exhibited better IGR activity
than corresponding chloro substitute. For both the series, Cl or F
groups at ortho position conferred better activity than its substitu-
As seen from table 2, BCTU 4c, 4d, 4e, 4f and BCU 5b, 5c showed
antifungal activity against these fungi. BCTU derivatives 4a, 4b and
BCU 5a, 5d, 5e, 5f were ineffective in controlling the growth of the
phytopathogens and food spoilage yeasts at the highest concentra-
tion tested. Secondly, the thiourea derivatives were more effective
than urea derivatives. The results of 4c, 5c indicated that presence
of chloride group at para position enhanced the antifungal activity.
No in vitro antifungal activity was observed for lufenuron, which is
in agreement with previous reports.6,7 As expected, carvacrol
showed good antifungal activity against all the tested organisms.
The hydroxyl group of carvacrol has been shown to have a special
role in the antimicrobial action of carvacrol.26
There are many reports on the use of carvacrol for the control of
human fungal pathogens such as Candida albicans, Aspergillus niger,
Microsporum canis etc.13,27 Carvacrol is a US Food and Drug Admin-
istration approved safe food additive, and used as a flavouring
agent in different foods.28 Though initially developed as insecti-
cides, benzoylphenyl urea compounds were reported to possess
potent antitumor activity and are in clinical development for
cancer treatment.29,30 Few reports have indicated the potential of
lufenuron for the control of fungal pathogens in animals.31,32
Therefore, the BCTU and BCU derivatives were checked for
tion at para position. The LD50 of carvacrol was 33.3
while its incorporation in a BPU had significant effect as evident
from the comparable activity (<13 g/nymph) of the derivatives
4b, 4d, 4e, 4f and 5d, 5f with the standard BPU lufenuron
(9.0 g/nymph).
lg/nymph,
l
l
The purified final compounds were evaluated for antifungal sus-
ceptibility testing by microbroth dilution method according to the
recommendations of the National Committee for Clinical Labora-
tory standards (NCCLS).25 The antifungal activity was tested using
the plant pathogenic fungal strains Magnporthe grisea, Fusarium
oxysporum, Dreschlera oryzae and food spoilage yeasts Debaromyces
hansenii, Pichia membranifaciens. Rice is the host for M. grisea and D.
oryzae, whereas F. oxysporum infests diverse plants including to-
mato, tobacco, legumes, cucurbits, sweet potatoes and banana. D.
hansenii and P. membranifaciens occur on grapes and are common
wine spoilage yeasts. The antifungal activities of the tested
Table 2
Antifungal susceptibility testing of BCTU and BCU derivatives against phytopathogenic fungi
Derivative
Minimum inhibitory concentration (MIC in lg/ml)
Phytopathogenic fungi
Food spoilage yeasts
P. membranifaciens
M. grisea
F. oxysporum
D. oryzae
D. hansenii
4a
4b
4c
4d
>512
>512
256
256
256
>512
>512
128
128
128
>512
>512
>512
>512
256
>512
>512
256
256
256
512
512
512
>512
512
4e
4f
5a
5b
5c
>512
>512
>512
512
>512
>512
512
256
>512
256
128
>512
128
>512
>512
256
256
128
128
256
5d
5e
5f
Lufenuron
Carvacrol
>512
>512
>512
>512
128
>512
>512
>512
>512
64
>512
>512
>512
>512
64
>512
>512
>512
>512
128
>512
>512
>512
>512
128

U. D. Pete et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5550–5554
5553
Table 3
Antifungal susceptibility testing of BCTU and BCU derivatives against human fungal pathogens
Compound
Growth Inhibitory concentration in
lg/ml
C. albicans NCIM
3557
C.
C. albicans NCIM
3471
C. glabrata NCIM
3237
C.
neoformans 3541
C. neoformans NCIM C. neoformans NCIM C. neoformans NCIM
albicans
3542
3378
4a
4b
4c
128
64
64
32
64
16
>512
>512
32
32
64
32
64
128
64
16
32
8
32
64
32
128
>512
32
ad
4e
4f
5a
5b
5c
5d
5e
128
64
256
512
128
64
>512
>512
>512
>512
128
128
64
64
>512
256
32
16
16
16
>512
128
>512
>512
>512
>512
>512
>512
32
32
32
>512
256
128
64
64
>512
>512
32
16
16
16
>512
128
32
16
64
32
32
>512
256
32
<4
<4
128
64
64
256
128
32
16
16
16
>512
128
512
128
128
>512
128
32
16
16
16
>512
128
512
>512
256
64
>512
>512
>512
>512
128
5f
<4
>512
128
Lufenuron
Carvacrol
antifungal activity against different strains of human pathogens C.
albicans, Candida glabrata and Cryptococcus neoformans
(Table 3). C. albicans and C. neoformans were isolates from clinical
samples whereas other strains and C. glabrata were procured from
National Centre for Industrially Important Microorganisms (NCIM),
Pune, India. All the BCTU derivatives showed potent antifungal
activity against these human pathogens. From BCU series, 5d, 5e
and 5f were most effective, whereas compounds 5a and 5b showed
weak or no antifungal activity against the tested strains. For most
of the compounds the activity was better than carvacrol against
human pathogens.
As stated earlier, carvacrol affects the cell membranes and re-
sults in depletion of sterols. Therefore, major concern of employ-
ing these newly synthesized compounds as crop protection or
antifungal agents is their potential toxicity to mammalian cells.
Hence, cellular toxicity of the compounds was checked by haem-
olysis assay as described previously.33 The concentrations tested
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.07.
017.
References and notes
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6. Johnson, S. M.; Zimmermann, C. R.; Kerekes, K. M.; Davidson, A.; Pappagianis, D.
Med. Mycol. 1999, 37, 441.
7. Scotty, N. C.; Evans, T. J.; Giuliano, E.; Johnson, P. J.; Rottinghaus, G. E.;
Fothergill, A. W.; Cutler, T. J. J. Vet. Intern. Med. 2005, 19, 878.
8. Enomoto, S.; Asano, R.; Iwahori, Y.; Narui, T.; Okada, Y. Biol. Pharm. Bull. 2001,
24, 307.
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11. Mueller-Riebau, F.; Berger, B.; Yegen, O. Agric J. Food Chem. 1995, 43, 2262.
12. Kordali, S.; Cakir, A.; Ozer, H.; Cakmakci, R.; Kesdek, M.; Mete, E. Bioresour.
Technol. 2008, 99, 8788.
13. Chami, N.; Chami, F.; Bennis, S.; Trouillas, J.; Remmal, A. Braz. J. Infect. Dis. 2004,
8, 217.
14. Pinto, E.; Pina-Vaz, C.; Salgueiro, L.; Goncalves, M. J.; Costa-de-Oliveira, S.;
Cavaleiro, C.; Palmeira, A.; Rodrigues, A.; Martinez-de-Oliveira, J. J. Med.
Microbiol. 2006, 55, 1367.
15. Rao, A.; Zhang, Y.; Muend, S.; Rao, R. Antimicrob. Agents Chemother. 2010, 54,
5062.
16. Lee, S. G.; Kim, S. I.; Ahn, Y. J.; Kim, J. B.; Lee, B. Y. Pestic. Sci. 1997, 49, 119.
17. Tang, X.; Chen, S.; Wang, L. Nat. Prod. Res. 2011, 25, 320.
18. Shah, H.; Vashi, S.; Mehta, S. Indian J. Che. 1995, 34B, 802.
19. Kremers, E.; Wakeman, N.; Hixon, R. Org. Syn. 1941, 1, 511.
20. General synthetic procedure for the synthesis of 4a–f: To a hot, vigorously
stirred solution of ammonium thiocyanate (0.84 g, 0.011 mol) in dry acetone
(20 mL), substituted benzoyl chloride (0.011 mol) in dry acetone (10 mL) was
added drop wise. The reaction mixture was stirred on a hot plate for 1.5 h and
it was added to an equimolar quantity of the 4-aminocarvacrol (1.82 g,
0.011 mol) in dry acetone (10 mL). The mixture was refluxed for 5–6 h at 55 °C.
The solvent was then removed under reduced pressure and the reaction
mixture was diluted with ice cold water (50 mL) to afford the product. The
separated solid was purified by recrystallization from hexane–ethyl acetate
mixture. Yields obtained are about 70 to 80%.
21. General synthetic procedure for the synthesis of 5a–f: Respective thioureas
(0.0033 mol) were dissolved in DMF and 85 % (15 mL) formic acid and 30%
hydrogen peroxide (50 mL) were slowly added to the solution. The reaction
mixture was stirred overnight and poured onto crushed ice. The precipitate
was collected, dried and recrystallized from hexane–ethyl acetate mixture to
afford the product.
were in the range of 4–1000
50% haemolysis (HC50) for all the BCTU, BCU compounds and
lufenuron was >1000 g/ml. Maximum haemolysis observed was
17% for compound 4e at 1000 g/ml concentration. At MIC con-
centrations for all the derivatives, the haemolysis was negligible
(<2%). The HC50 values for carvacrol and a similarly acting anti-
lg/ml. The concentration causing
l
l
fungal drug Amphoterecin B were 250 and 8 lg/ml, respectively.
The antifungal activity and haemolysis results indicated that the
synthesized compounds are better and safer than BPU’s and
carvacrol.
In conclusion, two series of BCTU and BCU derivatives were syn-
thesized by structurally modifying carvacrol and introducing ben-
zoylphenyl urea linkage. Derivatives 4b, 4d, 4e, 4f and 5d, 5f
showed comparable Insect growth regulator activity with the stan-
dard BPU lufenuron against D. koenigii. Most of the compounds
demonstrated potent antifungal activity against human pathogens
and potent to moderate activity against different phytopathogens
and food spoilage yeasts. All the compounds were non-haemolytic.
The synthesized compounds have a potential application in agri-
culture as safer and broad spectrum crop protection agents. After
comprehensive evaluation, they may also be used for the control
of fungal pathogens in veterinary and human healthcare.
Acknowledgments
22. Data for 1-benzoyl-3-(4-hydroxy-2-methyl-5-isopropylphenyl) thiourea (4a):
White solid, mp 208 °C, 1H NMR (300 MHz, CDCl3, 25 °C): d = 1.22 (d,
J = 6.87 Hz, 6 H, CH(CH3)2), 2.24 (s, 3 H, CH3), 3.05 (m, 1 H, CH(CH3)3), 5.06
(bs, 1 H, OH), 6.77 (s, 1 H, H-Ar), 7.27 (s, 1 H, H-Ar), 7.55 (t, 1 H, H-Ar), 7.64 (t, 2
H, H-Ar), 7.91 (d, J = 7.32 Hz, 2 H, H-Ar), 9.26 (bs, 1 H, NH), 11.98 (brs, 1 H, NH)
ppm. LC–MS calcd for C18H21N2O2S [M+H]+ 329.44 , found 329.00. C18H20N2O2S
(328.44): C, 65.83; H, 6.14; N, 8.53; S, 9.76; found C, 66.22; H, 6.17; N, 8.49.
Mr. Umesh Pete and Ratnamala Bendre are thankful to
University Grants Commission, New Delhi, India, for the financial
assistance. Santosh Tupe and Preeti Chaudhary thanks Council of
Scientific and Industrial Research, India for the research fellowship.

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U. D. Pete et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5550–5554
23. Data for 1-benzoyl-3-(4-hydroxy-2-methyl-5-isopropylphenyl) urea (5a):
White solid, mp 242 °C, 1H NMR (300 MHz, DMSO-d6, 25 °C): d = 1.13 (d,
J = 6.86 Hz, 6 H, CH(CH3)3), 2.46 (s, 3 H, CH3), 3.35 (m, 1 H, CH(CH3)2), 6.69 (s,1
H, H-Ar), 7.30 (s, 1 H, H-Ar), 7.50 (t, 1 H, H-Ar), 7.59 (t, 2 H, H-Ar), 7.99(d, 2 H,
H-Ar), 9.13 (s, 1 H,OH), 10.36 (brs, 1 H, NH), 10.93 (brs, 1 H, NH) ppm. LC–MS
calcd. for C18H21N2O3 [M+H]+ 313.37, found 313.20. C18H20N2O3 (312.37): C,
69.21; H, 6.45; N, 8.97; found C, 68.54; H, 5.77; N, 8.98.
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