Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents

Article abstract of DOI:10.1111/cbdd.13739

Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug-resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options availabl

Full text of DOI:10.1111/cbdd.13739

DR OLUSEYE ONAJOLE (Orcid ID : 0000-0002-4485-9648)
Article type
: Research Letter
Design, Synthesis and biological evaluation of novel
imidazo[1,2-a]pyridinecarboxamides as potent anti-
tuberculosis agents
Oluseye K. Onajole,a* Shichun Lun,b Young Ju Yun,c Damkam Y. Langue,a Michelle Jaskula-Dybka,a
Adrian Flores,a Eriel Frazier,a Ashle C. Scurry,a Ambernice Zavala,a Karen R. Arreola,a Bryce
Pierzchalski,a A. Jean-Luc Ayitou,c William R. Bishai,b,d*
aDepartment of Biological, Physical and Health Sciences, Roosevelt University, 425 S. Wabash Avenue,
Chicago, Illinois 60605, USA.
bCenter for Tuberculosis Research, Dept. of Medicine, Div. of Infectious Disease, Johns Hopkins School of
Medicine, Baltimore, MD 21231-1044, USA.
cDepartment of Chemistry, Illinois Institute of Technology, 3101 S. Dearbon Street, Chicago, Illinois 60616,
USA.
dHoward Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland, 20815-6789, USA.
ABSTRACT
Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The
emergence of multidrug resistant strains of TB has been detrimental to the fight against tuberculosis with very
few safe therapeutic options available. As part of an ongoing effort to identify potent anti-tuberculosis agents,
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/CBDD.13739
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we synthesized and screened a series of novel imidazo[1,2-a]pyridinecarboxamide derivatives for their anti-
tuberculosis properties. These compounds were designed based on reported anti-tuberculosis properties of the
indolecarboxamides (I2Cs) and imidazo[1,2-a]pyridinecarboxamides (IPAs). In this series, we identified
compounds 15 and 16 with excellent anti-TB activity against H37Rv strain of tuberculosis (MIC = 0.10 – 0.19
M); these compounds were further screened against selected clinical isolates of Mtb. Compounds 15 and 16
showed excellent activities against multidrug resistant (MDR) and extensively drug resistant (XDR) strains of
TB (MIC range: 0.05 – 1.5 M) with excellent selectivity indices. In addition, preliminary ADME studies on
compound 16 showed favorable pharmacokinetic properties.
INTRODUCTION
Tuberculosis (TB) is an insidious and air-borne infectious disease caused by Mycobacterium tuberculosis that
mainly affects the lungs. TB is one of the top 10 leading cause of mortality worldwide from a single infectious
disease (above HIV/AIDS). In 2018, the World Health Organization (WHO) estimated about 10 million people
fell ill with TB worldwide while 1.5 million died as a result of TB infection (0.25 million among people living with
HIV).(1) An estimated 0.9 million new cases of TB among people living with HIV was reported in 2018, 72% of
whom lived in Africa.(1) In addition, eight counties namely: India, China, Indonesia, Philippines, Pakistan, Nigeria,
Bangladesh and South Africa, accounted for two third of new TB cases reported globally.(1) The global health
burden of TB infection is further aggravated by HIV co-infection, thus making TB one of the leading cause of death
among people living with HIV.(1, 2) Active drug-susceptible TB is treatable and curable using a standard 6 month
course of 4 antimicrobial drugs (first-line anti-TB drugs namely isoniazid, rifampin, pyrazinamide and ethambutol),
however the long duration of treatment, poor drug quality, inability to provide the required drug regimens for the
duration of treatment and/or inappropriate drug use has given rise to the emergence of multi-drug resistant (MDR)
and extensively drug-resistant (XDR) TB.(2) The burden of TB is further exacerbated by the emergence of MDR-
TB and XDR-TB and current TB drugs are inadequate in putting an end to this multidrug resistance epidemic.
In August 2019, the FDA approved PA-824 (pretomanid) in combination with TMC207 (bedaquiline) and
Linezolid for the treatment of certain type of extremely treatment-resistant TB of the lungs.(3) Noteworthy,
TMC207 (bedaquiline; approved 2012) was the first anti-TB drug approved in over four decades by the FDA
for treatment of MDR-TB in adults when there are no other alternatives. However, bedaquiline (TMC207) is
associated with side effect such as irregular heart rhythm,(4) which show that the search for newer, highly
efficient, fast acting drug with low toxicity is far from over. Bedaquiline targets the membrane-bound
adenosine triphosphate (ATP) synthase enzyme of M. tuberculosis,(5-7) while the exact target of pretomanid is
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not yet known. Pretomanid was also reported to show activity against both replicating and hypoxic
nonreplicating strains of tuberculosis.(7-9)
Our TB drug discovery campaign led to the identification of indole-2-carboxamides which showed excellent
activity against susceptible, MDR and XDR strains of Mtb.(10-12) The indole-2-carboxamides has been
reported to inhibit Mtb growth by targeting the MmpL3 protein (which belongs to the resistance, nodulation
and cell division (RND) family of membrane transporters), an essential membrane transporter.(10-14) In
addition, we recently reported that indole-2-carboxamide (1) showed anti-M. abscessus activity by acting on
the MmpL3 protein of this organism.(15, 16)
Another heterocyclic aromatic carboxamide, which has been extensively researched as a highly potent anti-TB
scaffold, is the imidazopyridine-3-carboxamides (IPA).(17-24) Using genome sequencing technique, it was
established that IPA inhibitor family exert its anti-TB properties by targeting M. tuberculosis QcrB, an
essential component of the electron transport chain.(25)
Structural Activity Relationship (SAR) studies of the indole-2-carboxamides (I2C) showed the importance of
cyclic aliphatic ring on the amide nitrogen(10, 12) in order to enhance and maintain activity, this motivated us
to investigate the anti-TB activity of IPAs with varying size of cyclic aliphatic rings on the amide nitrogen at
both positions 2 and 3 of the imidazopyridine ring. Herein, we report the design, synthesis, biological
evaluation and in vitro pharmacokinetic (PK) of novel imidazo[1,2-a]pyridine carboxamide derivatives 3 – 19,
our goal is to design and investigate small molecules with potent anti-TB activity.
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Figure 1. Indole-2-carboxamide derivative 1; Imidazo[1,2-a]pyridine-3-carboxamide derivative 2 and hybrid
structure.
CHEMISTRY
Following efficient amide coupling protocol (Scheme 1), seventeen novel imidazopyridine carboxamide
derivatives were generated. Briefly, ethyl acetoacetate or ethyl benzoylacetate was reacted with N-
bromosuccinimide (NBS) to afford the corresponding ethyl-2-bromoacetoacetate or ethyl-2-
bromobenzoylacetate, which was subsequently reacted with substituted 2-amino pyridine (21-23) to afford the
various substituted imidazo[1,2-a]pyridine-3-carboxylates. Basic hydrolysis of the ester derivatives afforded
the corresponding acids 24 - 27.
The substituted imidazopyridine carboxylic acids (24 – 28) were reacted with their corresponding cycloalkyl
amines in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and
hydroxybenzotriazole (HOBt) as coupling agents and triethylamine as a base to obtain compounds 219
(Scheme 1).
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Scheme 1a
aReagents and conditions: (a) (i) ethyl acetoacetate or ethyl benzoylacetate, NBS, H2O, reflux, 1.5 h (ii)
substituted 2-aminopyridine, reflux, 3 h; (b) LiOH, EtOH, reflux, 3 h; (c) EDC.HCl, HOBt, corresponding
amine, Et3N, CH2Cl2, rt, 12–16 h, yield: 33 - 77%.
DISCUSSION
Structure-Activity Relationships: In general, the biological activity of the analogs was found to depend on
the number of carbon spacers between the amide Nitrogen and the cyclic aliphatic ring. The reference
compound 2 showed similar anti-TB activity (MIC = 0.2 μM) as reported in literature.(25) Replacement of the
aromatic side chain on the amide nitrogen with cyclic aliphatic rings such as N-cyclohexyl, N-cycloheptyl and
N-cyclooctyl groups (compounds 3 – 5) resulted in a loss of activity against susceptible strain of Mtb.
Furthermore, replacing the methyl group at position 6 of the imidazo[1,2-a]pyridine ring with a chloro group at
positions 6 or 7 (compounds 6 and 7) did not improve their activities against TB (MIC >200 M). In addition,
replacing the methyl group at 2-position of the imidazo[1,2-a]pyridine ring with a phenyl group (compound 8)
did not show any improved activity (MIC > 160 M).
Compounds 9 - 11 bearing one carbon spacer between the amide nitrogen and the cycloalkyl moieties (i.e.
cyclohexyl, cycloheptyl and cyclooctyl groups) turned out to be 267-, 133- and 133-fold more potent against
M.tb compared to their counterparts compounds 3 - 5 with no carbon spacers. On the other hand, compound 12
bearing one carbon spacer between the amide nitrogen and a polycyclic group (1-adamantyl derivative) showed
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poor anti-TB activity compared to its monocyclic counterparts 9 – 11. To complete the investigation of the
effect of the carbon spacer between amide nitrogen and cycloalkyl group, a two and three carbon spacers were
installed and investigated. Compounds 13 (bearing a cyclohexyl group) and 14 (bearing a cycloheptyl group)
with two carbon spacers showed similar activities as their one carbon spacer counterparts 9 and 10. On the
other hand, compound 15 (bearing a cyclohexyl group) with a three carbon spacers was 4-fold more active than
compounds 9 (one carbon spacer) and 13 (two carbon spacers) respectively. Switching the methyl group at
position 6 of compound 15 to a 6-chloro (compound 16) resulted in approximately 2-fold drop in activity,
while switching the methyl group at position 2 on the imidazopyridine ring to a phenyl group (compound 17,
with chloro substituent at position 7) resulted in a complete loss in activity, suggesting that a methyl or small
group at the 2-position is essential for activity. Noteworthy, compounds 15 and 16 were approximately 1.5 - 3-
fold more active than isoniazid against H37Rv strain of TB. Next, we examined the effect of the position of
the amide group on the imidazopyridine ring. The amide group at position 2 of the imidazo[1,2-a]pyridine ring
(18 and 19) proved to be less active than the amide group at position 3, implying that amide substituent at the
position 3 is essential for anti-TB activity.
Table 1. MIC Values of Imidazo[1,2-a]pyridine carboxamide analogs
MICa
MICa
(µM)
Compd
X
Y
R
Compd
X
Y
R
(µM)
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2
3
6-methyl methyl
6-methyl methyl
6-methyl methyl
6-methyl methyl
0.22
117.91
56.06
12
13
6-methyl methyl
6-methyl methyl
6-methyl methyl
6-methyl methyl
47.41
0.42
4
14
0.40
5
106.88
>200.13
200
15
0.10
6
6-chloro
7-chloro
7-chloro
methyl
methyl
phenyl
16
6-chloro
7-chloro
7-chloro
7-chloro
methyl
0.19
7
17
phenyl
>161.66
209.29
>200.13
0.29
8
18
-
-
167.58
0.44
9
6-methyl methyl
6-methyl methyl
6-methyl methyl
19
10
11
0.42
INHb
0.80
aThe lowest concentration of drug leading to at least a 90% reduction of bacterial growth signal by
the microplate AlamarBlue assay (MABA). MIC values are reported as an average of three individual
measurements; bINH = Isoniazid.
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Based on our preliminary results, the most active compounds (15 and 16) were selected for further screening
against a panel of clinical isolates(26) of Mtb originally obtained from pulmonary TB patients (Table 2).
Among those strains are one drug-sensitive (DS) (V4207), two MDR Mtb (KZN494 and V2475), two XDR
Mtb (TF274, R506) respectively. In addition, the toxicity of these compounds against mammalian cells was
evaluated on Vero cells, and their respective selectivity indices (SI) were calculated (Table 2). Compounds 15
and 16 maintained their excellent activity or showed only a moderate drop in activity (up to 2- fold for 15 and
up to 8-fold for 16) against the tested clinical isolates of Mtb. Noteworthy is the fact that both compounds (15
and 16) showed a 2-fold increase in activity against the MDR Mtb strain KZN494 while compounds 15
maintained its excellent activity against XDR Mtb strain R506. The high activity of these compounds against
MDR and XDR strains of TB indicates their potential use to treat drug-resistant Mtb strains. In addition,
compounds 15 and 16 displayed high IC50 values against Vero cells resulting in high SI indices suggesting their
potential lack of toxicity towards mammalian cells.
As for the mode of action, the imidazo[1,2-a]pyridinecarboxamides (IPAs) are well known QcrB inhibitors of
M. tuberculosis,(18, 22, 25, 27) thus we propose that these novel imidazo[1,2-a]pyridinecarboxamide
compounds could potentially target and bind to QcrB, which encodes the beta subunit of the cytochrome bc1
complex of Mycobacterium tuberculosis. The cytochrome bc1 facilitates electron transfer and proton [H+]
translocation, which is the driving force for ATP synthesis and essential for Mycobacterium tuberculosis.
Table 2. Activity of imidazo[1,2-a]pyridine-3-carboxamides against Selected Clinical Isolates of Mtb [MIC
(M)] and Vero Cells [IC50 (M)].
Mtb MIC (M)
Compd H37Rv/DS V4207/DS KZN494/MDRa V2475/MDRa R506/XDRb TF274/XDRb Vero cells IC50 SIc
(M)
15
16
0.10
0.19
0.10
0.37
0.05
0.09
0.20
0.37
0.10
0.75
0.20
1.5
102.07
1024
191.67
1024
b
aResistance to isoniazid and rifampin. Resistance to isoniazid, rifampin, levofloxacin, and kanamycin.
cSelectivity index (SI) = IC50 (Vero)/MIC.
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Preliminary ADME Studies on Compound 16.
Based on the encouraging biological results described above, we conducted some selected ADME studies on
compound 16 to assess its drug-like properties (Table 3). The compound exhibited high plasma protein binding
in human (99.89%) and mouse (99.64%). As shown in Table 3, in the presence of compound 16 (10 μM) none
of the tested CYP isoforms (with the exception of CYP3A4) showed greater than 48% inhibition.
Table 3. ADME data for imidazo[1,2-a]pyridine-3-carboxamide 16.
Assay
16
Plasma
protein
binding
(%),
99.89/99.64
human/mouse
CYP inhibition (% inhibition at 10 μM)
CYP1A2
CYP2C9
26.3
32.2
CYP2C19
45.2
CYP2D6
16.4
CY3A4a
52.2
hERG IC50 (μM)
>10
Hepatocytes, % remaining at 2 hrs,
0.19 (human)
starting concentration 1 M
Liver microsomes, % remaining after 1.51 (human, 60 mins), 0.15 (mouse, 60 mins)
1 hr, starting concentration 1 M
aMidazolam is used as substrate
The potential inhibitory effect of compound 16 on human Ether-à-go-go related gene (hERG) channel was
evaluated using manual patch-clamp system. Based on the result, compound 16 is suggested to be ranked as a
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weak inhibitor on hERG channel (low inhibition of hERG (IC50 > 10 μM); thus implying low potential risk for
blocking the cardiac calcium channel. Noteworthy, in the Ether-hERG analysis we found that compound 16
may encounter solubility problem in hERG assay buffer at the highest concentration, 30 M. The IC50 is
therefore only estimated to be > 10 M, as percentage hERG inhibition tested at 10 M was found less than
50% (29.10% inhibition at 10 M).
When incubated with human hepatocyte, over 95% of compound 16 degraded after 2 hours incubation using a
starting concentration of 1 M and the human hepatocytes. Compound 16 was unstable in liver microsomes
with approximately 1.5% (human) and 0.15% (mouse) remaining unchanged after 1 hour using a starting
concentration of 1 μM.
In summary, we describe the synthesis, structure-activity relationships and preliminary ADME analysis of
novel imidazo[1,2-a]pyridinecarboxamide derivatives as anti-TB agents. Modifications to the N-
methylthiophen-2-yl group at position 3 of the imidazo[1,2-a]pyridine ring in the lead compound 2 have been
explored to create compounds with improved biological activities. Compounds 15 and 16 were identified as the
most potent compounds in the series against susceptible strain of tuberculosis, and further screening of these
compounds (15 and 16) showed excellent activity against MDR and XDR clinical isolates of TB. In addition,
compound 16 showed acceptable PK properties, further study is currently underway to improve its stability in
liver microsome and hepatocyte. These compounds adds to the growing list of imidazopyridine carboxamide
derivatives that have been reported to possess anti-TB properties in literature(17, 18, 20, 22-24, 27-30).
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Experimental details
1. Chemistry method
General information. 7-chloroimidazo[1,2-a]pyridine-2-carboxylic acid was purchased from Combi-blocks.
1H NMR and 13C NMR spectra were recorded on a Bruker spectrometer (300 and 75 MHz), with TMS as an
internal standard. Standard abbreviation indicating multiplicity was used as follows: s = singlet, d = doublet, dd
= doublet of doublets, t = triplet, q = quadruplet, m = multiplet and br = broad. HRMS experiments were
performed on micOTOF-Q (Bruker) instrument. TLC was performed with Merck 60 F254 silica gel plates.
Flash chromatography was performed using YamazenFlash® Rf system with Yamazen pre-packed columns or
alternatively using Sigma-Aldrich silica gel (230–400 mesh). Purities of final compounds were established by
analytical HPLC, which was carried out using the Agilent 1100 HPLC system with a Synergi 4 μm Hydro-RP
80A column, on a variable wavelength detector G1314A. Method: flow rate = 1.0 mL/min; gradient elution
over 20 minutes, from 30% MeOH-H2O to 100% MeOH with 0.05% TFA, and 100% MeOH with 0.05% TFA
for an additional 5 minutes. The purity of all tested compounds was >95% (unless otherwise stated) as
determined by the method described above.
General procedure for the synthesis of 2-19
To a solution of the appropriate carboxylic acid (1 equiv) in anhydrous dichloromethane (CH2Cl2) (4
mL/mmol) at room temperature were added anhydrous hydroxybenzotriazole (HOBt, 1 equiv) and 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 1 equiv) under an argon atmosphere. After
stirring for 10 min, the appropriate substituted amine (1 equiv) and triethylamine (1.5 equiv) were added, and
the reaction mixture was stirred at room temperature until disappearance of the starting material (usually 12 to
16 h). After this time water (2 mL) was added, and the mixture was extracted with EtOAc (3×10 mL), the
organic layers were separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography (dichloromethane–methanol)
gradient, 0-10% methanol in dichloromethane over 20-30 minutes (unless specified differently) to obtain the
imidazopyridinamides in yields ranging from 33 to 77%.
Experimental details
2,6-dimethyl-N-(thiophen-2-ylmethyl)imidazo[1,2-a]pyridine-3-carboxamide (2). Yield 65% (off-white solid).
HPLC: tR 8.0 min, purity 98.6%. 1H NMR (300 MHz, CDCl3) δ 9.21 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.23
(d, J = 3.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.98-6.95 (t, J = 3.0, 6.0 Hz, 1H), 6.19
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(s, 1H), 4.86 (d, J = 6.0 Hz, 2H), 2.65 (s, 3H), 2.35 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.4, 145.5, 145.1,
141.1, 130.1, 127.0, 126.0, 135.3, 123.0, 115.7, 114.9, 38.3, 18.4, 16.8. HRMS (ESI) calcd for C15H16N3OS
([M+H]+) 286.1009; found: 286.0986.
N-cyclohexyl-2, 6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (3). Yield 70 % (white solid). HPLC: tR 9.0
min, purity 97.9%. 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 9.0 Hz,
1H), 5.67 (d, J = 6.0 Hz, 1H), 4.08-3.93 (m, 1H), 2.61 (s, 3H), 2.33 (s, 3H), 2.11-1.99 (m, 2H), 1.81-1.67 (m,
13
2H), 1.55-1.16 (m, 6H); C NMR (75 MHz, CDCl3) δ 160.9, 144.9, 144.5, 129.7, 125.9, 122.7, 115.6, 115.4,
48.1, 33.4, 25.6, 24.8, 18.3, 16.6. HRMS (ESI) calcd for C16H22N3O ([M+H]+) 272.1757; found: 272.1744.
N-cycloheptyl-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (4). Yield 74 % (white powder). HPLC: tR
10.3 min, purity 97.9%. 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 9.0
Hz, 1H), 5.74 (d, J = 6.0 Hz, 1H), 4.29-4.10 (m, 1H), 2.66 (s, 3H), 2.33 (s, 3H), 2.15-1.98 (m, 2H), 1.76-1.44
(m, 10H); 13C NMR (75 MHz, CDCl3) δ 160.7, 144.9, 144.5, 129.7, 125.9, 122.7, 115.7, 115.4, 50.4, 35.4,
28.0, 24.2, 18.3, 16.7. HRMS (ESI) calcd for C17H24N3O ([M+H]+) 286.1914; found: 286.1911.
N-cyclooctyl-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (5). Yield 61 % (white powder). HPLC: tR 12.5
min, purity 98.7%. 1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 9.0 Hz,
1H), 5.82 (d, J = 9.0 Hz, 1H), 4.28-4.20 (m, 1H), 2.66 (s, 3H), 2.32 (s, 3H), 1.95 (m, 2H), 2.02-1.60 (m, 12H).
13C NMR (75 MHz, CDCl3) δ 160.5, 146.0, 144.8, 144.1, 129.9, 125.9, 122.9, 115.5, 49.4, 32.5, 27.2, 25.5,
23.7, 18.3, 16.5. HRMS (ESI) calcd for C18H26N3O ([M+H]+) 300.2070; found: 300.2072.
6-chloro-N-cyclooctyl-2-methylimidazo[1,2-a]pyridine-3-carboxamide (6). Yield 50 % (white powder). HPLC: tR
15.3 min, purity 97.8%. 1H NMR (300 MHz, CDCl3) δ 9.49 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 3.0
Hz, 1H), 5.78 (d, J = 6.0 Hz, 1H), 4.32-4.15 (m, 1H), 2.68 (s, 3H), 2.03-1.99 (m, 2H), 1.71-1.61 (m, 12H). 13C
NMR (75 MHz, CDCl3) δ 160.1, 145.3, 144.1, 128.0, 126.1, 121.4, 116.6, 116.2, 49.5, 32.5, 27.2, 25.5, 23.7,
16.6. HRMS (ESI) calcd for C17H23ClN3O ([M+H]+) 320.1524; found: 320.1531.
7-chloro-N-cyclooctyl-2-methylimidazo[1,2-a]pyridine-3-carboxamide (7). Yield 51 % (white powder). HPLC: tR
13.9 min, purity 97.9%. 1H NMR (300 MHz, CDCl3) δ 9.17 (d, J = 6.0 Hz, 1H), 7.41 (s, 1H), 6.76 (d, J = 6.0
Hz, 1H), 5.85 (d, J = 6.0 Hz, 1H), 4.19-4.13 (m, 1H), 2.57 (s, 3H), 1.91-1.86 (m, 2H), 1.65-1.48 (m, 12H).; 13C
NMR (75 MHz, CDCl3) δ 160.0, 145.5, 145.4, 133.2, 128.1, 115.9, 115.2, 114.3, 49.4, 32.4, 27.1, 25.4, 23.6,
16.4. HRMS (ESI) calcd for C17H23ClN3O ([M+H]+) 320.1524; found: 320.1537.
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7-chloro-N-cyclooctyl-2-phenylimidazo[1,2-a]pyridine-3-carboxamide (8). Yield 56 % (white powder). HPLC: tR
19.7 min, purity 97.7%. 1H NMR (300 MHz, CDCl3) δ 9.62 (s, 1H), 7.67-7.64 (m, 2H), 7.61 (d, J = 9.0 Hz,
1H), 7.51-7.49 (m, 3H), 7.34 (d, J = 9.0 Hz, 1H), 5.82 (d, J = 9.0 Hz, 1H), 4.12-4.07 (m, 1H), 1.77-1.71 (m,
2H), 1.51-1.27 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 159.5, 148.3, 144.4, 133.5, 129.7, 129.6, 129.0, 128.5,
126.4, 121.9, 117.3, 115.4, 49.2, 31.4, 27.2, 25.3, 23.3. HRMS (ESI) calcd for C22H25ClN3O ([M+H]+)
382.1681; found: 382.1701.
N-(cyclohexylmethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (9). Yield 58 % (off-white solid).
1
HPLC: tR 10.8 min, purity 99%. H NMR (300 MHz, CDCl3) δ 9.19 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.15
(d, J = 9.0 Hz, 1H), 5.86 (s, 1H), 3.35-3.31 (t, J = 6.0, 6.0 Hz, 2H), 2.67 (s, 3H), 2.33 (s, 3H), 1.81-1.60 (m,
13
6H), 1.32-1.14 (m, 3H), 1.06-0.96 (m, 2H).; C NMR (75 MHz, CDCl3) δ 161.8, 145.0, 144.6, 129.8, 126.0,
122.8, 115.6, 115.3, 45.6, 38.1, 31.0, 26.4, 25.8, 18.3, 16.7. HRMS (ESI) calcd for C17H24N3O ([M+H]+)
286.1914; found: 286.1895.
N-(cycloheptylmethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (10). Yield 47 % (off-white powder).
HPLC: tR 12.4 min, purity 98.3%. 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.17
(d, J = 9.0 Hz, 1H), 5.85 (s, 1H), 3.37-3.33 (t, J = 6.0, 6.0 Hz, 2H), 2.69 (s, 3H), 2.34 (s, 3H), 1.91-1.71 (m,
4H), 1.72-1.68 (m, 2H), 1.58-1.45 (m, 5H), 1.34-1.24 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.8, 145.0,
144.6, 129.8, 126.0, 122.8, 115.7, 115.4, 45.9, 39.8, 32.3, 28.3, 26.4, 18.4, 16.7. HRMS (ESI) calcd for
C18H26N3O ([M+H]+) 300.2070; found: 300.2058.
N-(cyclooctylmethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (11). Yield 72 % (off-white powder).
1
HPLC: tR 11.9 min, purity 99%. H NMR (300 MHz, CDCl3) δ 9.12 (s, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.11
(d, J = 9.0 Hz, 1H), 5.91 (s, 1H), 3.30-3.26 (t, J = 6.0, 6.0 Hz, 2H), 2.63 (s, 3H), 2.29 (s, 3H), 1.79-1.27 (m,
15H); 13C NMR (75 MHz, CDCl3) δ 161.7, 144.9, 144.6, 129.7, 125.9, 122.7, 115.6, 115.4, 46.1, 37.9, 30.4,
26.9, 26.2, 25.4, 18.3, 16.6. HRMS (ESI) calcd for C19H28N3O ([M+H]+) 314.2227; found: 314.2213.
N-(adamantan-1-ylmethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (12). Yield 73 % (tan solid).
1
HPLC: tR 12.5 min, purity 99%. H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.14
(d, J = 9.0 Hz, 1H), 5.87-5.82 (t, J = 6.0, 9.0 Hz, 1H), 3.19 (d, J = 6.0 Hz, 2H), 2.70 (s, 3H), 2.31 (s, 3H), 2.05-
1.96 (m, 3H), 1.73-1.56 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 161.9, 145.0, 144.5, 129.7, 126.0, 122.8,
115.6, 115.4, 50.7, 40.4, 36.9, 33.9, 28.2, 18.3, 16.9. HRMS (ESI) calcd for C21H28N3O ([M+H]+) 338.2227;
found: 338.2212.
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N-(2-cyclohexylethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (13). Yield 51 % (off-white powder).
HPLC: tR 12.6 min, purity 98.5%. 1H NMR (300 MHz, CDCl3) δ 9.12 (s, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.11
(d, J = 9.0 Hz, 1H), 5.82-5.79 (t, J = 3.0, 6.0 Hz, 1H), 3.50-3.43 (q, J = 6.0, 6.0, 9.0 Hz, 2H), 2.65 (s, 3H), 2.32
(s, 3H), 1.74-1.60 (m, 5H), 1.53-1.46 (q, J = 6.0, 21.0, 12.0 Hz, 2H), 1.33 (m, 1H), 1.22-1.15 (m, 3H), 0.98-
0.90 (t, J = 12.0, 12.0 Hz, 2H).; 13C NMR (75 MHz, CDCl3) δ 160.6, 144.9, 144.6, 129.7, 125.9, 122.7, 115.6,
115.3, 37.3, 35.6, 33.2, 26.4, 26.2, 18.3, 16.6. HRMS (ESI) calcd for C18H26N3O ([M+H]+) 300.2070; found:
300.2073.
N-(2-cycloheptylethyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (14). Yield 33 % (tan solid). HPLC:
tR 14.2 min, purity 96.6%. 1H NMR (300 MHz, CDCl3) δ 9.07 (s, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.10 (s, J =
9.0 Hz, 1H), 5.89-5.85 (t, J = 6.0, 6.0 Hz, 1H), 3.46-3.40 (q, J = 6.0, 6.0 Hz, 2H), 2.59 (s, 3H), 2.26 (s, 3H),
1.71-1.32 (m, 13H), 1.22-1.13 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.6, 144.8, 144.6, 129.6, 125.8, 122.7,
115.5, 115.3, 37.9, 37.7, 37.0, 34.4, 28.4, 26.3, 18.3, 16.5. HRMS (ESI) calcd for C19H28N3O ([M+H]+)
314.2227; found: 314.2220.
N-(3-cyclohexylpropyl)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (15). Yield 77 % (tan solid). HPLC:
tR 14.0 min, purity 98%. 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 9.0
Hz, 1H), 5.81-5.77 (t, J = 6.0, 6.0 Hz, 1H), 3.49-3.42 (q, J = 6.0, 9.0, 6.0 Hz, 2H), 2.66 (s, 3H), 2.33 (s, 3H),
13
1.74-1.62 (m, 7H), 1.31-1.12 (m, 6H), 0.93-0.83 (m, 2H); C NMR (75 MHz, CDCl3) δ 161.7, 144.9, 144.7,
129.8, 125.9, 122.8, 115.7, 115.4, 39.8, 37.4, 34.8, 33.3, 27.3, 26.6, 26.3, 18.3, 16.7. HRMS (ESI) calcd for
C19H28N3O ([M+H]+) 314.2227; found: 314.2224.
6-chloro-N-(3-cyclohexylpropyl)-2-methylimidazo[1,2-a]pyridine-3-carboxamide (16). Yield 55 % (off-white
powder). HPLC: tR 17.7 min, purity 97.8%. 1H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H), 7.52 (d, J = 12.0 Hz,
1H), 7.30 (d, J = 12.0 Hz, 1H), 5.84-5.83 (t, J = 3.0, 3.0 Hz, 1H), 3.51-3.44 (q, J = 6.0, 6.0, 6.0 Hz, 2H), 2.69
(s, 3H), 1.70-1.68 (m, 7H), 1.28-1.18 (m, 6H), 0.95-0.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 161.1, 145.3,
144.1, 128.2, 126.1, 121.5, 116.6, 116.1, 39.9, 37.3, 34.7, 33.3, 27.2, 26.6, 26.3, 16.5. HRMS (ESI) calcd for
C18H25ClN3O ([M+H]+) 334.1681; found: 334.1672.
7-chloro-N-(3-cyclohexylpropyl)-2-phenylimidazo[1,2-a]pyridine-3-carboxamide (17). Yield 70 % (tan powder).
HPLC: tR 20.5 min, purity 93.8% 1H NMR (300 MHz, CDCl3) δ 9.65 (s, 1H), 7.68-7.61 (m, 3H), 7.52-7.51
(m, 3H), 7.37-7.33 (m, 1H), 5.81 (s, 1H), 3.31-3,24 (q, J = 6.0, 9.0, 6.0 Hz, 2H), 1.69-1.61 (m, 7H), 1.43-1.33
(m, 2H), 1.22-1.10 (m, 4H), 1.05-0.97 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.6, 148.4, 144.5, 133.5,
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128.7, 129.1, 128.7, 126.8, 126.4, 122.0, 117.4, 115.2, 39.6, 37.3, 34.5, 33.2, 26.6, 26.5, 26.3. HRMS (ESI)
calcd for C23H27ClN3O ([M+H]+) 396.1837; found: 396.1837.
7-chloro-N-cyclooctylimidazo[1,2-a]pyridine-2-carboxamide (18). Yield 46 % (white powder). HPLC: tR 17.5
min, purity 96.4%. 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 8.11 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.28 (d, J
= 6.0 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 4.20-4.17 (m, 1H), 1.97-1.90 (m, 2H), 1.71-1.57 (m, 12H); 13C NMR
(75 MHz, CDCl3) δ 161.0, 142.8, 141.4, 127.4, 124.2, 121.5, 118.4, 114.4, 49.2, 32.2, 27.3, 25.4, 23.7. HRMS
(ESI) calcd for C16H21ClN3O ([M+H]+) 306.1368; found: 306.1358.
7-chloro-N-(3-cyclohexylpropyl)imidazo[1,2-a]pyridine-2-carboxamide (19). Yield 61 % (white powder). HPLC:
tR 18.7 min, purity 97.8%. 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 8.11 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H),
7.35-7.34 (t, 1H), 7.23 (d, J = 9.0 Hz, 1H), 3.47 (q, J = 6.0, 6.0, 6.0 Hz, 2H), 1.68-1.61 (m, 7H), 1.29-1.16 (m,
6H), 0.93-0.86 (m, 2H).; 13C NMR (75 MHz, CDCl3) δ 162.1, 142.8, 141.2, 127.5, 124,2, 121.7, 118.4, 114.4,
39.6, 37.4, 34.6, 33.3, 27.1, 26.7, 26.3. HRMS (ESI) calcd for C17H23ClN3O ([M+H]+) 320.1524; found:
320.1532.
2. Biological method
Minimum Inhibitory Concentration (MIC) determination. MIC was determined by using MABA assay.
Mtb H37Rv and five clinical isolates were cultured to mid-log phase (OD600 = 0.5) in 7H9 broth at 37ºC. The
culture was diluted to OD600 of 0.001 using 7H9 without Tween 80 targeting 105 colony forming units (CFU)
per mL. Two-fold serial dilution was made for compounds from 64 to 0.0039 µg/mL using 100 µL of 7H9
without Tween 80 on 96-well plates. One hundred µL of the above-mentioned diluted culture was added to
each testing wells. Test plates were incubated at 37 ºC for 7 days, then 32.5 µL of alamarBlue reagent was
added to all wells. Plates were further incubated for 16-18 h at 37o and read at Ex544/Em590 using a BMG
Optima fluorescence plate reader. Data were analyzed and the lowest concentration that inhibited 90% of
growth was defined as MIC.
Vero Cytotoxicity (IC50) determination. Cytotoxicity of selected compounds, expressed as IC50, was
determined using Vero cells and MABA assay. Briefly, Vero cell linage (ATCC CCL-81) was grown in
Dulbecco’s Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (FBS). Flat-bottomed 96-
well plate was seeded with 1 × 104 cells per well. The plate was incubated at 37oC with 5% CO2 for 16 h. For
compound preparation, 2-fold serial dilution was made using a deep-well block using DMEM containing 5%
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FBS with a volume of 200 µL. Culture media was replaced with 160 µL of the compound-containing media,
with 100% DMSO as positive (100% kill) control and media-only as blank (100% viability) control. The plate
was incubated for 72 h and then washed twice with PBS before adding 100 µL of DMEM with 5% FBS
medium freshly mixed with 10% alamarBlue. The plate was incubated for 2 h and then immediately read with
a fluorescence microplate reader at 544Ex/590Em. The minimum concentration that killed at least 50% of the
cells was identified as IC50.
Acknowledgment
O.K.O. acknowledge financial support for this project from Roosevelt University Faculty Startup fund and the
2019 Roosevelt University Summer Grant. O.K.O. and A.F. acknowledges the Roosevelt University Ronald E.
McNair Post-Baccalaureate Achievement Program for its generous financial support. This material is also
based upon work supported by the National Science Foundation under a CAREER grant no. 1753012 awarded
to A.J.A. NIH funding grants AI37856 and HL133190 to W.R.B.
*Authors for correspondence: Oluseye K. Onajole (medicinal chemistry): E-mail: oonajole@roosevelt.edu;
William R. Bishai (biological screening): E-mail: wbishai1@jhmi.edu
Conflict of Interest
The authors declare that there are no conflicts of interest regarding this work
Data availability statement
The data that support the findings of this study are available from the corresponding authors upon reasonable
request.
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