Facile microwave-assisted synthesis and antitubercular evaluation of novel aziridine derivatives

Article abstract of DOI:10.1016/j.molstruc.2021.130038

Novel 2-(aryloxymethyl)aziridines and 2-((3-aryl-1-phenylallyloxy)methyl)aziridine derivatives were prepared via ring-opening reaction of epoxides. The synthesized derivatives were characterized by using elemental analysis (EA), FT-IR, ¹³C NMR, and ¹H NMR. The in vitro antitubercular activities of the synthesized compounds were evaluated against Mycobacterium tuberculosis H37Rv (MTB H37Rv) strain using MTT-MABA assay. All the aziridine derivatives exhibited improved persuasive antitubercular activity against MTB H37Rv in comparison with standard drugs. Among the tested compounds, 2-(naphthalene-1-yloxy) methyl aziridine (5b), 2-(naphthalene-2-yloxy)methylaziridine (5c), 2-(m-tolyloxymethyl)aziridine (5e), 2-(3-(4-methoxyphenyl)-1-phenylalloxy)methylaziridine (12b) and 2-(3-(2-chlorophenyl)-1-phenylallyloxy)methylaziridine (12c) revealed promising activity against MTB H37Rv. Specifically, compound 5b and 12 b showed three-times more active (MIC = 0.5 μg/mL) than the standard drugs ethambutol (MIC = 1.56 μg/mL) and ciprofloxacin (MIC = 1.56 μg/mL).

Full text of DOI:10.1016/j.molstruc.2021.130038

Journal of Molecular Structure 1233 (2021) 130038
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Facile microwave-assisted synthesis and antitubercular evaluation of
novel aziridine derivatives
Perumal Sarojinia, Malaichamy Jeyachandranb,∗, Dharmarajan Sriramc,
Palraj Ranganathand, S Gandhimathib
a Department of Chemistry, Sri Ramasamy Naidu Memorial College, Sattur, 626203, Tamil Nadu, India
b Post Graduate and Research Department of Chemistry, Sri Paramakalyani College, Alwarkurichi, (Affiliated to Manonmaniam Sundaranar University)
Tirunelveli 627 412, Tamil Nadu, India
c Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar 500 078, Hyderabad, India
d Institute of Organic and Polymeric Materials, National Taipei University of Technology, No. 1, Sec. 3, Chung-Hsiao East Road., Taipei, 10608, Taiwan (ROC)
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 2-(aryloxymethyl)aziridines and 2-((3-aryl-1-phenylallyloxy)methyl)aziridine derivatives were pre-
pared via ring-opening reaction of epoxides. The synthesized derivatives were characterized by us-
ing elemental analysis (EA), FT-IR, 13 C NMR, and 1H NMR. The in vitro antitubercular activities of
the synthesized compounds were evaluated against Mycobacterium tuberculosis H37Rv (MTB H37Rv)
strain using MTT-MABA assay. All the aziridine derivatives exhibited improved persuasive antitu-
bercular activity against MTB H37Rv in comparison with standard drugs. Among the tested com-
pounds, 2-(naphthalene-1-yloxy) methyl aziridine (5b), 2-(naphthalene-2-yloxy)methylaziridine (5c), 2-
(m-tolyloxymethyl)aziridine (5e), 2-(3-(4-methoxyphenyl)-1-phenylalloxy)methylaziridine (12b) and 2-(3-
(2-chlorophenyl)-1-phenylallyloxy)methylaziridine (12c) revealed promising activity against MTB H37Rv.
Specifically, compound 5b and 12 b showed three-times more active (MIC = 0.5 μg/mL) than the standard
drugs ethambutol (MIC = 1.56 μg/mL) and ciprofloxacin (MIC = 1.56 μg/mL).
Received 12 June 2020
Revised 29 January 2021
Accepted 31 January 2021
Available online 2 February 2021
Keywords:
Aziridine derivatives
Ring-opening
Microwave-assisted
Anti-TB activity
MTB H37Rv
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
TB (comprising children with HIV-positive related TB, WHO, 2018).
After a certain period, the pathogen resisted the two most power-
Tuberculosis (TB) is one of the most contagious air-borne dis-
eases caused by Mycobacterium tuberculosis (MTB), causing more
deaths than any other infection worldwide [1]. Conferring to uni-
versal TB, Report-2018 TB is one of the topmost 10 reasons of hu-
man demise globally in 2017 [2]. The current therapy comprises of
longstanding multi-drug combination that is non-compliant with
treatment and leads to associated adverse side effects. Various
studies led by the World Health Organization (WHO) divulge 10
million people suffer from MTB and 1.6 million dies from it (com-
prising 0.3 million in HIV patients) [3-5]. MTB is a prominent
killer of HIV-positive patients and a vital cause of antimicro-
bial resistant-related death. TB is cured with complex therapeu-
tic drugs, which comprises several antibiotics that target differ-
ent cellular processes. According to the WHO, the global TB re-
ports estimate that in 2017, women 3.2 million, men 5.8 million,
and children 1.0 million suffer from TB and 2, 30,000 died from
ful drugs, such as fluoroquinolones and rifampicin. Universally in
2017, 558,000 peoples were exposed to TB and 160,000 multidrug
resistance (MDR-TB/RR-TB) and rifampicin resistance (RR-TB) [6,7].
However, there are many anti-tubercular drug molecules in the
pipeline, but there is still an urgent necessity to scrutinize novel
anti-tubercular drug molecules to battle the peril of TB [8].
Over the past two decades, almost enormous quantities of natu-
ral products and organic synthetic products have been studied for
TB infections [9]. Of these, aziridines are of great interest due to
the following facts: aziridines are a group of nitrogenous species
related to epoxides and are natural and synthetic organic com-
pounds that have a three-membered heterocyclic ring with one
amine moiety [10-14]. The organic chemist considered the aziri-
dine system to be well known because of its tremendous potential
in both organic synthesis and medicinal chemistry [15-18]. Aziri-
dine nucleus occurs in several natural and many synthetic com-
pounds of biological and pharmacological interest [11,12].
From the multitude of contributions in the scientific literature
[13], it is clear that aziridines can be regarded as cherished com-
pounds from a clinical and synthetic point of view [14]. More-
∗
Corresponding author.
E-mail addresses: jeyachandranm@gmail.com (M. Jeyachandran), rangapalraj@
gmail.com (P. Ranganathan).
https://doi.org/10.1016/j.molstruc.2021.130038
0022-2860/© 2021 Elsevier B.V. All rights reserved.

P. Sarojini, M. Jeyachandran, D. Sriram et al.
Journal of Molecular Structure 1233 (2021) 130038
Scheme 1. Synthesis of 2-(aryloxymethyl) aziridines (5a-f).
Scheme 2. Synthesis of 2-((3-Aryl-1- phenylallyloxy)methyl)aziridine (12a-d).
over, the scope and application of aziridine compounds in chem-
istry have rapidly increased, as these classes of compounds have
drawn substantial attention owing to their biological properties. It
has been found that aziridine compounds play an important role as
therapeutic activities such as cytotoxic [19], antiviral [20], antifun-
gal [21], antimicrobial, antimalarial [22] and antitubercular proper-
ties [23] antiproliferative and antidiabetic activities [24]. Interest-
ingly, the synthesized aziridine derivatives showed better perfor-
mance than the conventional standard drugs. With this perspec-
tive, we have synthesized some novel compounds of aziridines and
evaluated them for antitubercular activity by the facile microwave-
assisted reaction method.
Non-conventional conditions and their approach to implement-
ing novel synthetic organic reaction become very popular, mainly
to avoid growing ecological concerns [25]. The literature shows
that scientists have ultimately contributed to the fast development
of novel chemical companies available for biological assessment.
The microwave-assisted reaction is a priceless technology for the
preparation of organic compounds over time because it reduces the
reaction time with improved selectivity and yields [26,27].
Therefore, the present work reports a facile microwave-assisted
synthesis of a new class of aziridine derivatives (5a-f and 12a-
d) via the ring-opening reaction of epoxides (Schemes 1 and 2).
The synthesized aziridine compounds were characterized (elemen-
tal analysis, FT-IR, 1H NMR, and 13C NMR) and studied as antitu-
bercular activity against MTB H37Rv strain.
Important clinical compounds that are synthesized through
facile steadfast reactions obtain the most fascinated attention.
2

P. Sarojini, M. Jeyachandran, D. Sriram et al.
2. Experimental
Journal of Molecular Structure 1233 (2021) 130038
NMR (500 MHz, CDCl3); δ (ppm) = 18.23, 28.11, 28.71, 71.12 (C–
C), 107.33, 120.84, 125.41, 126.05, 127.85, 128.54, 133.51, 133.63,
154.32. MS (EI, 70 eV): m/z (%) = 199. Elemental Anal.Calcd. (%) for
C13H13NO = C, 78.36; H, 6.58; N, 7.03; O, 8.03; found = C, 78.07;
H, 6.29; N, 6.77; O, 7.78.
2.1. Measurements and reagents
All the starting materials and precursors were used in this work
are analytical grade and are purchased from Sigma Aldrich. Fourier
Transform InfraRed spectra (FT-IR) measurements were recorded
on a Bruker Alpha FT-IR spectrophotometer with a frequency range
of 4000cm−1–500 cm−1 by the attenuated total reflection (ATR)
method. Data were collected over 64 scans with a resolution of 4
2.2.3.3. 2-(Naphthalene-2-yloxy) methylaziridine (5c). Yield: 65%. IR
(CHCl3) v/cm−1) = 3385, 2936, 2879, 2363, 2105, 1632, 1398,
1224, 1126, 1045, 966 and 845. 1H NMR (500 MHz, CDCl3); δ
(ppm) = 1.41, 1.67 (m, 2H, –CH2 of aziridine ring), 2.11 (m, 1H,
C’1–CH), 3.77, 3.52 (m, 2H, C’2–CH2), 7.48–7.97 (Ar-C). 13C NMR
(500 MHz, CDCl3); δ (ppm) = 23.04, 28.84, 70.83 (C–C), 118.11,
124.02, 126.63, 126.70, 126.91, 129.50, 129.64, 155.66. MS (EI,
70 eV): m/z (%) = 199 (Fig. S1). Elemental Anal.Calcd. (%) for
C13H13NO = C, 78.36; H, 6.58; N, 7.03; O, 8.03; found = C, 78.08;
H, 6.31; N, 6.75; O, 7.75.
cm−1. Carbon and proton nuclear magnetic resonance spectra (13
C
NMR and 1H NMR) were recorded with a Bruker 500 MHz at 25 °C,
with CDCl3 or DMSO–d6 as the solvent. Chemical shift (δ) and cou-
pling constants (J) are uttered in part per million (ppm) and hertz,
respectively. NMR data are given as several protons and multiplic-
ity: singlet (s), doublet (d), triplet (t), multiplet (m). Mass spectra
were performed on Shimadzu GCMS-QP 1000 EX mass spectrome-
ter (EI; 70 eV model). The elemental analysis (EA) was performed
on CHNS-932-LECO elemental analyzer.
2.2.3.4. 2-(ortho-Tolyloxymethyl)aziridine (5d). Yield: 70%. IR
(CHCl3) v/cm−1) = 3387, 2938, 2881, 2365, 2107, 1634, 1400, 1226,
1128, 1047, 968, 847. 1H NMR (500 MHz, CDCl3); δ (ppm) = 1.42,
1.65 (m, 2H, –CH2 of aziridine ring), 2.11 (m, 1H, C1’–CH), 2.15
(s, 3H, –CH3), 3.67, 3.42 (m, 2H, C2’–CH2), 6.89- 7.12 (Ar–C). 13C
NMR (500 MHz, CDCl3); δ (ppm) = 15.42, 23.00, 28.83, 70.81,
112.04, 120.24, 126.32, 126.78, 131.29, 155.47. MS (EI, 70 eV): m/z
(%) = 163. Elemental Anal.Calcd. (%) for C10H13NO = C, 73.59; H,
8.03; N, 8.58; O, 9.80; found = C, 73.34; H, 7.79; N, 8.35; O, 9.54.
2.2. Synthesis
2.2.1. General synthesis of 2-(aryloxymethyl)oxiranes (3a-f)
The general procedure for 3a-f synthesis was as follows. Into
a doubled-necked round-bottomed flask (100 mL) phenol com-
pounds (1a-f, shown in Scheme 1) (0.01 mol) and 20 mL of
epichlorohydrin (EPH) (2) were added, and the mixture was re-
fluxed for 180 min in the presence of a mild base (K2CO3). Sub-
sequently, the reaction mixture was cooled to ambient temper-
ature and then the excess EPH was eliminated under vacuum.
The achieved residue was poured into cold-water and mined with
ethyl acetate. Finally, the obtained 2-(aryloxymethyl)oxiranes (3a-f)
product was dried in an oven under a vacuum.
2.2.3.5. 2-(meta-Tolyloxymethyl)aziridine
(5e). Yield:
72%.
IR
(CHCl3) v/cm−1) = 3389, 2940, 2883, 2363, 2109, 1630, 1402, 1228,
1130, 1049, 970, 849. 1H NMR (500 MHz, CDCl3); δ ppm = 1.41,
ꢀ
1.66 (m, 2H, –CH2 of aziridine ring), 2.11 (m, 1H, C1 –CH), 2.34
ꢀ
(s, 3H, –CH3), 3.67, 3.42 (m, 2H, C2 –CH2), 6.79–7.22 (Ar–C).
13C NMR (500 MHz, CDCl3); δ ppm = 21.60, 23.02, 28.89, 70.88,
111.47, 113.01, 120.66, 129.29, 139.05, 157.34. MS (EI, 70 eV): m/z
(%) = 163. Elemental Anal. Calcd. (%) for C10H13NO = C, 73.59; H,
8.03; N, 8.58; O, 9.80; found = C, 73.33; H, 7.77; N, 8.32; O, 9.52.
2.2.2. General synthesis of 1-azido-3-(aryl) propane-2-ol (4a-f)
NaN3 (0.03 mol) and 2-(Aryloxymethyl)oxiranes (3a-f)
(0.01 mol) were dissolved in ethanol and water mixture in the
ratio of 50:50 vol% and stirred for 1 h. Subsequently, a pinch of
tetrabutylammonium bromide (TBAB) was introduced to the above
mixture to improve the completeness of the reaction. The obtained
product was treated with ice-cold water and separated with ethyl
acetate. Finally, the obtained 1-azido-3-(aryl) propan-2-ol (4 a-f)
product was dried in an oven under a vacuum.
2.2.3.6. 2-((4-Chlorophenoxy)methyl)aziridines (5f). Yield: 60%. IR
(CHCl3) v/cm−1): 3394, 2944, 2887, 2366, 2112, 1634, 1406, 1232,
1134, 1053, 974, 853. 1H NMR (500 MHz, CDCl3); δ ppm = 1.46,
ꢀ
1.65 (m, 2H, –CH2 of aziridine ring), 2.11 (m, 1H, C1 –CH), 3.67,
ꢀ
3.42(m, 2H, C2 –CH2), 7.03–7.38 (Ar–C). 13C NMR (500 MHz,
2.2.3. General synthesis of 2-(aryloxymethyl)aziridines (5a-f )
1-Azido-3-(aryl)propan-2-ols (4a-f) (0.01 mol) and triph-
enylphosphine (0.01 mol) were thoroughly mixed in ethanol, after
which the reaction mixture was subjected to microwave irradiation
yields 2-(aryloxymethyl) aziridines (5a-f, physical state: brown vis-
cous gel).
CDCl3); δ (ppm) = 23.23, 28.85, 70.82, 117.50, 125.99, 130.54,
157.51. MS (EI, 70 eV): m/z (%) = 183. Elemental Anal. Calcd.
(%) for C9H10ClNO = C, 58.86; H, 5.49; Cl, 19.31; N, 7.63; O,
8.71; found = C, 58.59; H, 5.23; N, 19.05; O, 8.43.
2.2.4. General synthesis of 3-aryl-1-phenylprop-2-en-1-one (8a-d)
The general procedure for 8a-d synthesis was as follows. To
a stirred alcoholic solution of acetophenone (6) in 10 mL of 95%
ethanol, aromatic aldehydes (7a-d) (0.01 mol) was added at room
temperature. Afterward, 6 mL of 10% NaOH solution was intro-
duced drop-wise to it. After stirring for 30 min, 20 mL of ice-cold
water was added to it. Finally, the obtained product (8a-d) was fil-
tered and recrystallized using aqueous ethanol.
2.2.3.1. 2-(Phenoxymethyl)aziridine (5a). Yield 70%. IR (CHCl3)
v/cm−1) = 3381, 2931, 2361, 2101, 1628, 1391, 1217, 1119, 1038,
959, 838. 1H NMR (500 MHz, CDCl3); δ (ppm) = 1.41, 1.67 (m,
2H, -CH2 of aziridine ring), 2.11 (m, 1H, C1’–CH), 3.67, 3.42 (m,
2H, C2’–CH2), 6.99–7.34 (Ar–H). 13C NMR (500 MHz, CDCl3); δ
(ppm) = 23.31, 28.83, 70.82 (C–C), 114.01 (C = C), 120.35 (C = C),
129.33 (C = C), 159.43 (Ar–C–O). MS (EI, 70 eV): m/z (%) = 149.
Elemental Anal. Calcd. (%) for C9H11 NO = C, 72.46; H, 7.43; N,
9.39; O, 10.72; found = C, 72.28; H, 7.17; N, 9.13; O, 10.43.
2.2.5. General synthesis of 3-aryl-1-phenylprop-2-en-1-ol (9a-d)
Into a doubled-necked round-bottomed flask (100 mL) a sus-
pension of 3-aryl-1-phenylprop-2-en-1-one (8a-d) (0.01 mol) and
sodium borohydride (0.02 mol) in ethanol (10 mL) was added and
refluxed for 180 min. Then, the reaction mixture was then poured
into ice-cold water, and extracted with ethyl acetate. Lastly, the ob-
tained product (9a-d) was dried in an oven under a vacuum.
2.2.3.2. 2-(Naphthalene-1-yloxy) methyl aziridine (5b). Yield 65%. IR
(CHCl3) v/cm−1) = 3386, 2936, 2880, 2366, 2106, 1633, 1396,
1222, 1124, 1043, 964 and 843. 1H NMR (500 MHz, CDCl3); δ
(ppm) = 1.44, 1.71 (m, 2H, –CH2 of aziridine ring), 2.11 (m,
1H, C’1–CH), 3.67, 3.45 (m, 2H, C2’–CH2), 6.68–8.36 (Ar–H). 13C
3

P. Sarojini, M. Jeyachandran, D. Sriram et al.
Journal of Molecular Structure 1233 (2021) 130038
2.2.6. General synthesis of 2-(1-phenyl-3-arylallyloxy)methyloxirane
(10a-d)
2.2.8.4. 2-(3-(3-Nitrophenyl)−1-phenylallyloxy) methylaziridine (12d).
Yield: 75%. IR (CHCl3) v/cm−1) = 3384, 3060, 2877, 2400, 2344,
1634, 1399, 1187, 1123, 1046, 727 and 700. 1H NMR (500 MHz,
CDCl3); δ (ppm) = 1.40 & 1.66 (m, 2H, –CH2 of aziridine ring), 1.93
To a solution of 1–chloro-2, 3-epoxypropane (5 mL), 3-aryl-
1-phenylprop-2-en-1-ol (9a-d) (0.01 mol), and sodium metal
(0.02 mol) were added into the round-bottomed flask and refluxed
for 90 min. Afterward, the mixture was filtered, extracted and
the solvent was eliminated under vacuum condition. The obtained
residue was treated with cold water and extracted with diethyl
ether. Finally, the achieved product (10a-d) was dried in an oven
under a vacuum.
ꢀ
ꢀ
(m, 1H, C1 –CH), 3.58, 3.33 (m, 2H, C2 –CH2), 4.31 (m, 1H, –CH of
allyl), 6.91, 6.48 (m, 2H, –C = H of allyl), 7.48–8.31 (Ar–C). 13C NMR
(500 MHz, CDCl3); δ (ppm) = 23.04, 29.61, 78.75, 81.14, 124.63,
127.48, 128.69, 129.57, 134.60, 136.16, 147.86. MS (EI, 70 eV): m/z
(%) = 310. Elemental Anal. Calcd. (%) for C18 H18 N2O3 = C, 69.66; H,
5.85; N, 9.03; O, 15.47; found = C, 69.42; H, 5.59; N, 8.78; O, 15.21.
2.2.9. Antitubercular studies
2.2.7. General synthesis of 1-azido-3-(3-aryl-1-phenylallyloxy)
propan-2-ol (11a-d)
Synthesized aziridine derivatives were screened against MTB
H37Rv using MTT-MABA assay [28]. The inoculum was made by
employing a new LJ medium re-suspended in the 7H9-S medium.
Originally, the 7H9-S medium was prepared by 7H9 broth in 0.1%
casitone, oleic acid, 0.5% glycerol, albumin, catalase [OADC], and
dextrose. The prepared medium attuned to a McFarland tube No.
1 and it was diluted to 1:20; 100 μL and employed as inoculum.
The prepared stock solution was defrosted and diluted in 7H9-S
at four-fold the last uppermost concentration verified. A germ-free
96-well microliter plate using 100 μl 7H9-S was used to prepare
the two-fold dilutions of each drug. Growth control comprising no
antibiotic and a germ-free control were also fortified on each plate.
To evade evaporation during incubation, germ-free water was em-
ployed in all the perimeter wells. Lastly, the resultant plates were
covered, sealed in plastic bags, and incubated at 35 °C under nor-
mal conditions. After one week of incubation, 30 mL of alamarBlue
solution was added to each well, and again the plate was subjected
to re-incubation overnight. The variation in color from blue (oxi-
dized state) to pink (reduced) exposed the growth of bacteria and
the MIC value was well-defined as the lowermost concentration of
drugs that avert this color alteration.
To a solution of 2-(1-phenyl-3-arylallyloxy)methyl oxirane (10a-
d) (0.01 mol), a solution of sodium azide (0.03 mol) in 50:50 vol%
of water and ethanol and a pinch of TBAB were added and the
reaction mixture was constantly agitated for 60 min. Subsequently,
the reaction mixture was poured into ice-cold water and extracted
with ethyl acetate. Finally, the achieved product 11a-d was dried
in on over under a vacuum.
2.2.8. General synthesis of
2-((3-aryl-1-phenylallyloxy)methyl)aziridine (12 a-d)
Compounds 11a-d (0.01 mol) and triphenylphosphine
(0.01 mol) were thoroughly mixed in ethanol, after which the
reaction mixture was subjected to microwave irradiation yields 12
a-d (physical state: brown viscous gel).
2.2.8.1. 2-(1, 3-Diphenylallyloxy)methylaziridine (12a). Yield: 70%.
IR (CHCl3) v/cm−1
1176, 1119, 1038, 719 and 690. 1H NMR (500 MHz, CDCl3); δ
)
=
3376, 2931, 2361, 2078, 1628, 1391,
(ppm) = 1.40, 1.68 (m, 2H, -CH2 of aziridine ring), 1.93 (m,
ꢀ
ꢀ
1H, C1 –CH), 3.77, 3.52 (m,2H, C2 –CH2), 4.31 (m, 1H, -CH of al-
3. Results and discussion
lyl), 6.64, 6.38 (m, 2H, –C = H of allyl, 7.27–7.44 (Ar–C). 13C
NMR (500 MHz,CDCl3); δ (ppm)
=
23.19, 29.67, 78.71, 81.11,
3.1. Characterization
124.64, 127.28, 127.83, 129.04, 136.42, 139.87. MS (EI, 70 eV): m/z
(%) = 265. Elemental Anal. Calcd. (%) for C18 H19NO = C, 81.47; H,
7.22; N, 5.28; O, 6.03; found = C, 81.22; H, 6.97; N, 5.02; O, 5.77.
The synthetic pathway adopted for the construction of novel
2-(aryloxymethyl) aziridines (5a-f) was displayed in Scheme 1.
The different phenols (1a-f) were refluxed with EPH in the ex-
istence of K2CO3 to yield their 2-(aryloxymethyl) oxiranes (3a-
f). Aryloxymethyl)oxiranes (3a-f) were prepared by condensa-
tion of excess phenols or substituted phenols with epichloro-
hydrin. The obtained 3a-f were further reacted with sodium
azide to yield the azido alcohols (4a-f). During the above ring-
opening reaction [29-31], the sodium azide attacks the oxirane
species on less substituted methylene groups through an SN2
mechanism produces 4a-f. Further, the reaction of 4a-f with
triphenylphosphine on microwave irradiation resulted in the for-
mation of title compounds 2-(aryloxymethyl)aziridines (5a-f) by
the condensation reaction. The obtained products are namely,
2-(phenoxymethyl)aziridine (5a), 2-(naphthalene-1-yloxy) methyl
aziridine (5b), 2-(naphthalene-2-yloxy)methylaziridine (5c), 2-
(o-tolyloxymethyl)aziridine (5d), 2-(meta-tolyloxymethyl)aziridine
(5e), and 2-((4-chlorophenoxy)methyl)aziridines (5f) are in good
yield.
2.2.8.2. 2-(3-(4-Methoxyphenyl)−1-phenylalloxy)methylaziridine
(12b). Yield: 65%. IR (CHCl3) v/cm−1
)
=
3378, 3054, 2396,
2336, 2082, 1628, 1393, 1179, 1117, 1040, 721 and 695. 1H NMR
(500 MHz, CDCl3); δ (ppm) = 1.69, 1.41 (m, 2H, –CH2 of aziridine
ring), 1.93 (m, 1H, C’1–CH), 3.77, 3.52 (m, 2H, C’2–CH2), 3.81 (s,3H,
–CH3), 4.31 (m,1H, –CH of allyl), 6.66, 6.37 (m, 2H, –C = H of allyl,
7.48–7.97 (Ar–C). 13C NMR (500 MHz, CDCl3); δ (ppm) = 23.20,
29.60, 55.85, 78.74, 80.19, 81.13, 124.69, 127.44, 128.63, 128.78,
129.11 (C = C), 129.64, 130.25, 39.93, 159.80. MS (EI, 70 eV): m/z
(%) = 283. Elemental Anal.Calcd. (%) for C19 H21NO2 = C, 77.26; H,
7.17; N, 4.74; O, 10.83; found = C, 77.02; H, 6.92; N, 4.48; O, 10.58.
2.2.8.3. 2-(3-(2-Chlorophenyl)−1-phenylallyloxy)methylaziridine (12c).
Yield: 70%. IR (CHCl3) v/cm−1): 3380, 3057, 2398, 2338, 2084, 1630,
1395, 1181, 1119, 1042, 723 and 697. 1H NMR (500 MHz, CDCl3);
δ (ppm) = 1.46, 1.71 (m, 2H, –CH2 of aziridine ring), 1.93 (m, 1H,
The presence of the aziridine group in structures of 5a-f was
confirmed by the presence of the IR band at around 2931–2940
cm−1. The compounds 5a-f (Fig. S2-S7) showed two multiplet at
δ 1.70 and 1.45 ppm due to the existence of CH2 and CH of the
aziridine ring. The presence of multiplet at δ 2.11 ppm due to the
ꢀ
ꢀ
C1 –CH), 3.58, 3.33 (m, 2H, C2 –CH2), 4.31 (m,1H, –CH of allyl),
6.64, 6.48 (m, 2H, –C = H of allyl), 7.32–7.44 (Ar–C). 13C NMR
(500 MHz, CDCl3); δ (ppm) = 23.44, 29.83, 78.79, 81.12, 126.61,
127.43, 127.85, 128.62, 129.18, 129.33, 129.91, 133.00, 134.95,
139.92. MS (EI, 70 eV): m/z (%) = 299. Elemental Anal. Calcd. (%)
for C18 H18 ClNO = C, 72.11; H, 6.05; Cl, 11.83; N, 4.67; O, 5.34;
found = C, 71.86; H, 5.79; Cl, 11.57; N, 4.43; O, 5.09.
ꢀ
presence of methine (C1 -CH) group. Similarly, the presence of a
methylene (C’2-CH2) group in compound 5a-f was confirmed by
the presence of δ 3.67 and 3.42 ppm. Further, the existence of
4

P. Sarojini, M. Jeyachandran, D. Sriram et al.
Journal of Molecular Structure 1233 (2021) 130038
Table 1
Antitubercular activity of the synthesized compounds 5a-f and 12 a-d (a; High potent antitu-
bercular compounds).
Compound
MIC(μg/mL)
Compound
MIC(μg/mL)
Compound
MIC(μg/mL)
5a
5b
5c
5d
5e
5f
13.7
0.5a
3.125a
12a
12b
12c
12d
11.5
Isoniazid
0.1
a
0.5
Rifampicin
Ethambutol
Ciprofloxacin
0.2
2.50a
1.56
1.56
7.25
15.75
a
1.25
25
an aromatic ring in the manufactured compounds (5a-f) was in-
dicated by the appearance of δ at 6.99 – 7.34 ppm region. 13C
NMR spectra analysis gave the signal at δ = 23.04 and 28.84 ppm
which is indicative of aziridine ring carbon. Similarly, the presence
of an aliphatic methylenic group whereas aromatic carbon group
in compound 5a-f were confirmed by the existence of δ = 114.4–
159.7 ppm.
which is three-times highly active than standard drugs, ethambu-
tol (MIC: 1.56 μg/mL), and ciprofloxacin (MIC: 1.56 μg/mL). The
existence of phenyl groups in its aziridine moiety exhibits good
anti-TB activity against MTB H37Rv. The role of phenyl groups in
its aziridine moiety in improving anti-TB activities is supported by
the studies of Zayane et al. [33].
The title compounds, novel 2-((3-aryl-1-phenylallyloxy)
methyl)aziridine (12a-d) have been prepared by the following
multi-step pathway, starting from aromatic aldehydes (Scheme 2).
The chalcones, 3-aryl-1-phenylprop-2-en-1-one (8a-d) was syn-
thesized by digesting acetophenone and aromatic aldehydes by
the addition of NaOH. 3-Aryl-1-phenylprop-2-en-1-one (8a-d)
was then careful reduction with sodium borohydride in refluxed
ethanol solution and achieved 3-aryl-1-phenylprop-2-en-1-ol (9a-
d). A solution of 1–chloro-2, 3-epoxypropane, 3-aryl-1-phenylprop-
2-en-1-ol (9a-d), and sodium metal mixture were refluxed for
getting the respective 2-(1-phenyl-3-arylallyloxy)methyloxirane
(10a-d). The obtained 2-(1-phenyl-3-arylallyloxy)methyloxirane
(10a-d) were reacted with NaN3 in the existence of TBAB to yield
their 1-azido-3-(3-aryl-1-phenylallyloxy) propan-2-ol (11a-d).
When the microwave irradiation of the 1-azido-3-(3-aryl-1-
phenylallyloxy) propan-2-ol (11a-d) with triphenylphosphine gave
the title compounds, 2-((3-aryl-1-phenylallyloxy) methyl)aziridine
(12 a-d) with moderate to better yield.The obtained prod-
uct are namely, 2-(1, 3-diphenylallyloxy)methylaziridine (12a),
2-(3-(4-ethoxyphenyl)−1-phenylalloxy)methylaziridine (12b), 2-(3-
(2-Chlorophenyl)−1-phenylallyloxy)methylaziridine (12c), 2-(3-(3-
Nitrophenyl)−1-phenylallyloxy) methylaziridine (12d).
3.3. Molecular docking studies
The anti-TB screening revealed that the compounds 5b, 5e, and
12b exhibited good activity against MTB H37Rv. Keep in mind
that all the compounds obtained are newly synthesized, there is
no literature information regarding their biological function. Pre-
diction of Functional Spectrum for Material (PASS) was used to
gain a sense of their potential activity online program. This in-
strument is invented to offer possible biological activity based on
the compound’s molecular structure. The receptor 5UHA was se-
lected for docking studies. To determine whether the docking pa-
rameters were adequate, flexible ligand-rigid enzyme simulation
was performed with 5UHA. The compound 5b interaction with
5UHA (Fig. 1) shows nitrogen atom of the aziridine moiety made
a conventional H-bond with Gly538, and the pi-donor hydrogen
The IR spectra of the aziridine derivative (12a-d) specify the
creation of products as it displays
a typical absorption peak
at around 2931–2940 cm−1, which corresponds to the aziridine
group. The 1H NMR spectra (Fig. S8-S11) of aziridine derivative
(12a-d) show chemical shift peaks, multiplets at around δ 1.66
& 1.46 ppm due to the -CH2 of aziridine ring and the peak at δ
7.27–8.31 ppm region for aromatic protons, respectively. The pres-
ence of two characteristics of carbon signals is witnessed at around
δ = 23.07 and 29.84 ppm in the 13C NMR spectrum of 12a-d owing
to the signals of aziridine ring carbons, confirming the successful
preparation of compounds 12a-d.
3.2. Biological studies
The in vitro anti-TB activity of synthesized compounds 5a-f and
12a-d against MTB H37Rv using the MABA assay and was evalu-
ated and their minimum inhibitory concentration (MIC) values are
tabulated in Table 1 at μg/mL [32]. From the outcomes of anti-
TB activity, all the synthesized compounds showed appreciable ac-
tivity compared to the standard drugs rifamycin, ethambutol, and
ciprofloxacin. However, compounds 5b (MIC: 0.5 μg/mL), 5c (MIC:
3.125 μg/mL), 5e (MIC: 1.25 μg/mL), 12b (MIC: 0.5 μg/mL), and
12c (MIC: 2.50 μg/mL) showed the highest potent activity against
MTB H37Rv in comparison with reference drugs. Compound 5b
and 12b also showed the highest potent activity (MIC: 0.5 μg/mL)
Fig. 1. Docking mode, hydrogen and non-hydeogen bonding interaction of the com-
pound 5b with 5UHA receptor.
5

P. Sarojini, M. Jeyachandran, D. Sriram et al.
Journal of Molecular Structure 1233 (2021) 130038
Fig. 3. Docking mode, hydrogen and non-hydrogen bonding interaction of the com-
pound 12b with 5UHA receptor.
Fig. 2. Docking mode, hydrogen and non-hydrogen bonding interaction of the com-
pound 5e with 5UHA receptor.
4. Conclusions
˚
bond has a bond distance of 2.42425 and 2.37381 A with ser428,
respectively. The compound 5b is encapsulated in a hydropho-
bic cavity formed by lys1040, ile1041, arg427, and val429 with
a bond length of 4.77356, 5.2971, 5.1705, 3.68931, and 5.43094,
respectively.
The present work describes
a
series of new 2-
and 2-((3-aryl-1-
(aryloxymethyl)aziridines (5 a-f)
phenylallyloxy)methyl)aziridines (12a-d) derivatives that were
synthesized by the ring-opening reaction of epoxides. The struc-
tures of the synthesized aziridine derivative 5a-f and 12a-d were
confirmed by various spectroscopic techniques and elemental
analysis. The synthesized compounds are screen for their in vitro
anti-TB activity against MTB H37Rv using the MABA assay. Among
these aziridine compounds, 5c, 5e, and 12c have displayed high
potent anti-TB activity against MTB H37Rv. Out of these screened
compounds, 5b and 12b were found to be the most potent in-
hibitor for MTB H37Rv. These compounds, 5b and 12b have shown
0.5 μg/mL MIC against MTB H37Rv which is three-time better
than standard drugs. Therefore, it can be concluded from the above
results that the prepared aziridine derivatives offer a fascinated
foremost series for the invention of novel anti-TB agents.
In addition to this π-alkyl hydrophobic interaction was shown
by lys1040, ile1041, arg427, and val429. In the second region of
5e and 5UHA (Fig. 2), three different types of interactions were
shown. π-alkyl and alkyl hydrophobic interactions amid ile1041,
ala1043, and leu446 have been shown. The interaction amid 5e
and glu450 has weak H-bonding interactions. In the hydropho-
bic chamber, alkyl-alkyl interaction was shown between ile1041
and leu446 with a 5e compound. Weak H-bonding interaction
is established between 5e and glu450. In the third region, hy-
drophobic activity formed by dg12, da13, dg13, and leu865 shows
π-sigma interactions with a bond distance of 5.5442, 5.61401,
˚
4.60537, 3.87417 A, respectively. Weak hydrogen bond interac-
tion occurs between arg465, arg869, and asp869 with a bond
˚
length of 3.69983, 3.48711, and 3.44505 A, respectively. In the
hydrophobic chamber (Fig. 3), aziridine moieties are situated via
Author statement
π donor-hydrogen bonding interaction between dg12 and dg13
˚
A
with 3.14882 and 3.30779
respectively. It is vital to high-
Our revised manuscript entitled Facile microwave-assisted
light that the examined compounds 5b, 5e, and 12b establish
hydrogen bonds with the 5UHA receptor. These facts described
the excellent anti-TB activity of aziridine compounds 5b, 5e, and
12b.
synthesis and antitubercular evaluation of novel aziri-
ꢀꢀ
dine derivatives”. “Ms. Ref. No.:
with the authors including “Perumal Sarojinia, Malaichamy
MOLSTRUC-d-20–02,638
Jeyachandranb∗, Dharmarajan Sriramc, Palraj Ranganathand, S
6

P. Sarojini, M. Jeyachandran, D. Sriram et al.
Journal of Molecular Structure 1233 (2021) 130038
Gandhimathib”, is the author done all the experimental, charac-
[15] D. Zych, A. Slodek, S. Krompiec, K. Malarz, A. Mrozek-Wilczkiewicz, R. Musiol,
ꢀ
ꢀ
ꢀ
ꢀꢀ
4 -phenyl-2, 2 : 6 , 2 -terpyridine derivatives containing 1-substituted-2, 3-tri-
azole ring: synthesis, characterization and anticancer activity, ChemistrySelect
3 (2018) 7009–7017.
terization, analysis, and wrote most part of the manuscript.
[16] A.M. Thompson, P.D. O’Connor, A. Blaser, V. Yardley, L. Maes, S. Gupta, D. Lau-
nay, D. Martin, S.G. Franzblau, B. Wan, Y. Wang, Repositioning antitubercular
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Declaration of Competing Interest
The authors declare no competing financial interest.
Acknowledgments
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7