Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis agents

Article abstract of DOI:10.1016/j.cclet.2015.03.027

Abstract Two series of phenothiazine derivatives were designed and synthesized. All compounds were tested for anti-tuberculosis activities against Mycobacterium tuberculosis H₃₇R_V. In comparison with mother compound of chlorpromazine, compound 6e shows promising anti-tuberculosis activity and much less mammalian cell cytotoxicity, compound 6e merits to be further explored as new anti-tuberculosis agents.

Full text of DOI:10.1016/j.cclet.2015.03.027

G Model
CCLET 3256 1–4
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Synthesis and bio-evaluation of phenothiazine derivatives as new
anti-tuberculosis agents
Q1 Chun-Xian He a, Hui Meng b, Xiang Zhang a, Hua-Qing Cui c, Da-Li Yin a,
*
5
6
a State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese
7
8
9
Academy of Medical Sciences, Beijing 100050, China
b College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
c Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking
10
Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Two series of phenothiazine derivatives were designed and synthesized. All compounds were tested for
anti-tuberculosis activities against Mycobacterium tuberculosis H37RV. In comparison with mother
compound of chlorpromazine, compound 6e shows promising anti-tuberculosis activity and much less
mammalian cell cytotoxicity, compound 6e merits to be further explored as new anti-tuberculosis
agents.
Received 1 December 2014
Received in revised form 4 January 2015
Accepted 4 March 2015
Available online xxx
ß 2015 Da-Li Yin. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of
Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
Keywords:
Phenothiazines
Anti-tuberculosis
Chlorpromazine
TMC207
11
12
1. Introduction
novel anti-tuberculosis agents with high efficacy and low toxicity, 32
particularly with different mode of actions compared to current 33
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Tuberculosis (TB) is a chronic infectious disease that seriously
threatens human health. Moreover, in the past decade worldwide
efforts have been made to treat TB due to the fast increasing
population of TB, the emergence of drug-resistant TB, and the
worldwide HIV and TB co-infection [1,2]. In 2012, it is estimated
that 8.6 million people developed the disease of TB, among them
13% were also proved to be HIV-positive. The situation becomes
more serious since an estimated of 450,000 people in 2012 devel-
oped multi-drug resistant TB (MDR-TB) and an estimated 170,000
died of MDR-TB [3].
Currently, regimens for the treatment of TB which the bacteria
are antibiotic susceptible must contain multiple first-line anti-
tuberculosis drugs such as isoniazid, rifampicin, pyrazinamide and
ethambutol [3]. Whereas, the treatment of multi-drug resistant TB
is more complicated, consists of what are called second-line drugs
which are more expensive than first-line drugs and have more
adverse effects [4]. Generally, the treatment procedure can take up
to two years, and one third of MDR-TB patients will unfortunately
eventually die of this disease [5]. Therefore, it is urgent to develop
existed anti-TB drugs.
34
Phenothiazines are in clinical use as an effective anti- 35
psychotic for the treatment of psychosis for about 60 years. 36
Interestingly, phenothiazines were also reported of in vitro 37
activities of anti-tumor [6], anti-bacterial [7], anti-plasmid [8] 38
and anti-tuberculosis [9,10]. Previous reports have demonstrated 39
in vitro and in vivo activity of some known phenothiazine 40
derivatives, such as promethazine, chlorpromazine (CPZ), tri- 41
fluoperazine and thioridazine (TZ) (Fig. 1) against drug-suscepti- 42
ble and drug-resistant TB bacteria [11,12]. There are also 43
confirmed reports of a TB patient cured with CPZ [13]. However, 44
significant side effects especially extrapyramidal motor symp- 45
toms (EPMS) which comprises Hyperkinetic-dystonic syndrome, 46
Parkinson syndrome and Tardive dyskinesia constrained the 47
application of phenothiazine derivatives in clinic [14]. Unfortu- 48
nately, these psychotic related side effects is likely associated 49
with or even a necessary condition for anti-psychotic efficacy 50
[14,15]. Moreover, the anti-tuberculosis MIC90 of CPZ analogs 51
ranges from 0.9 mg/L to 32 mg/L, which exceeds the maximum 52
safe serum level (0.5 mg/L) acceptable for the patient with 53
psychotic [9]. Thus, it is necessary to eliminate the anti-psychotic 54
efficacy and EPMS in order to develop this series of compounds as 55
*
Corresponding author.
E-mail address: yindali@imm.ac.cn (D.-L. Yin).
new anti-tuberculosis drugs (Fig. 2).
Q256
http://dx.doi.org/10.1016/j.cclet.2015.03.027
1001-8417/ß 2015 Da-Li Yin. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. All
rights reserved.
Please cite this article in press as: C.-X. He, et al., Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis
agents, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.03.027

G Model
CCLET 3256 1–4
2
C.-X. He et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
Fig. 3. The design strategy of series 2.
potency of TMC207 as anti-tuberculosis agents, we extracted part
of the moiety from TMC207 to replace the 10-substituted side
chain of CPZ and designed 3-(dimethylamino)-1-(3-fluorophenyl)-
1-(9H-thioxanthen-9-yl) propan-1-ol as depicted (Series 2) in Fig.
3.
91
92
93
94
95
Fig. 1. 10H-phenothiazine and phenothiazines.
2.2. Chemistry
96
The 1H NMR, 13C NMR, HMBC, HMQC, H-HCOSY, DEPT were
recorded on Mercury-300 and Mercury-400 spectrometer. Chemi-
97
98
99
100
101
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
The anti-tuberculosis activity of phenothiazine skeleton has not
yet been properly explored. However, comparison of SARs of anti-
tuberculosis and anti-psychotic obtained from limited phenothia-
zine derivatives suggests that anti-TB activity is mainly from the
scaffold of phenothiazine, since there is no obvious SAR trend can
be concluded from the side chain and substituents of related
phenothiazine derivatives [16,17]. It is revealed that the terminal
amine group in the 10-side chain as well as C-2 substitution
determines the optimal neuroleptic activity on central nervous
system [18].
With the clues of marginal anti-tuberculosis activity of
phenothiazine compounds, we proposed to discover new anti-
TB drugs by investigation of the relationship between the structure
of phenothiazine derivatives and their anti-tuberculosis activities
and further designed new compounds based on the information.
cal shifts are reported as
d
values with tetramethylsilane (TMS),
employed as the internal standard. HR-ESIMS data were measured
on Micromas AutoSpec Ultima-TOF spectrometer.
2.2.1. Series 1
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
N-Alkyl derivatives 2, 4, 5 in Series 1 were synthesized using
phenothiazine as the starting material (Scheme 1). Compounds 2
and 4 was obtained through reported procedure [22]. Methylation
of compound 4 with MeI/NaH gave 10-(3-methoxypropyl)-10H-
phenothiazine 5 in the yield of 79.6%. The synthesis of 6a–d was
achieved via the combination of phenothiazine with various
reagents. Treatment of phenothiazine with NaH and 1-bromobu-
tane or (3-bromopropoxy) benzene provided 6a and 6b in the
yields of 56.4% and 63.1% respectively. Treatment of phenothiazine
with 3-(1,3-dioxoisoindolin-2-yl)propanoyl chloride or benzoyl
chloride in pyridine at 50 8C afforded 6c and 6d in the yields of
95.0% and 81.0%. Compound 6d was prepared through the
treatment of phenothiazine with iodobenzene via coupling
reaction in 87.3% yield.
Scheme 1. Synthesis of compounds 2, 4, 5. Reagents and
conditions: (a) NaH, THF, room temperature 1 h, 80.4%; (b) KOH,
glycol/H2O, reflux 16 h, 82.0%; (c) H2SO4, EtOH, reflux 6 h, 99.4%;
(d) LiAlH4, THF, 5 h, 88.4%; (e) MeI, NaH, THF, 2 h, 79.6%; (f) for 6a
(56.4%) and 6b (63.1%): NaH, room temperature 2 h; for 6c (95.0%)
and 6d (81.0%): pyridine, 50 8C, 5 h; for 6e: Pd2(dba)3, DPPF,
NaOBu, toluene, 90 8C, 16 h, 87.3%.
The design of compounds 9a and 9b are aimed to slightly
modify the phenothiazine skeleton. Treatment 2(3H)-benzothia-
zolone with 1-bromopentane in NaOEt/EtOH under reflux afforded
the intermediate 7 in 86.5% yield. Followed by hydrolysis in KOH/
EtOH under reflux for 2 h, intermediate 8 was then prepared in
98.0% yield. The synthesis of compound 9a and 9b was
accomplished by condensation of 8 and cyclohexane-1,3-dione
or Tetronic Acid in 76.7% and 93.1% yields respectively. 9H-
thioxanthene analogs 11, 12a–12b were synthesized as described
in Scheme 2. The reduction of 9H-thioxanthen-9-one with sodium
72
73
2. Experimental
2.1. Inhibitor design
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
It is known that the side chain with an amino group is a
necessity for anti-psychotic activity of phenothiazine derivatives
[18,19], but it may not be necessary for anti-tuberculosis activity.
We first explored the possibility to change the side chain, including
removing the amino group. Then, further modification on the
tricyclic ring and the side chain will be carried out. For series 1, we
replaced 10-substituents with different non-basic substituents to
eliminate the corresponding side effects. In addition, based on
structure transformation of CPZ, we also did slightly modification
on the phenothiazine core to decrease the conjugation system or
replace phenothiazine with thioxanthenes and 9H-thioxanthene.
For series 2, we are aware of structure similarity of the basic
moiety of 10-substituted side chain between CPZ and TM207.
TMC207 was approved by the FDA with a MIC90 of 0.06
mg/mL in
2012 [20]. In mouse models of TB infection, TMC207 exceeded the
anti-tuberculosis activities of WHO recommended combination of
rifampin, isoniazid and pyrazinamide [21]. Given the highly
Fig. 2. The design strategy of series 1.
Please cite this article in press as: C.-X. He, et al., Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis
agents, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.03.027

G Model
CCLET 3256 1–4
C.-X. He et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
Scheme 1. Synthesis of compounds 2, 4, 5. Reagents and conditions: (a) NaH, THF, r.t. 1 h, 80.4%; (b) KOH, glycol/H2O, reflux 16 h, 82.0%; (c) H2SO4, EtOH, reflux 6 h, 99.4%; (d)
Scheme 2. Reagents and conditions: (a) NaOEt, 1-bromopentane, EtOH, reflux 4 h, 86.5%; (b) KOH, EtOH, reflux 2 h, 98.0%; (c) DMSO, 155 8C, 4 h; (d) sodium borohydride,
EtOH, reflux 3 h, 94.4%; (e) acetic acid, r.t. 2 h, 95.9%; (f) Zn, TiCl4, aldehyde (R-CHO), THF, reflux, 12a (38.2%), 12b (63.9%).
134
135
136
137
138
139
140
141
142
143
144
borohydride in EtOH gave the intermediate of 10 in 94.4% yield.
Followed by nucleophilic substitution with 1-(p-tolyl) urea,
compound 11 was afforded in 95.9% yield. Compounds 12a
and 12b were synthesized from 9H-thioxanthen-9-one with
3-hydroxy-4-methoxybenzaldehyde via McMurry reaction in the
yields of 38.2% and 63.9%, respectively.
Scheme 2. Reagents and conditions: (a) NaOEt, 1-bromopen-
tane, EtOH, reflux, 4 h, 86.5%; (b) KOH, EtOH, reflux, 2 h, 98.0%; (c)
DMSO, 155 8C, 4 h; (d) sodium borohydride, EtOH, reflux 3 h,
94.4%; (e) acetic acid, room temperature 2 h, 95.9%; (f) Zn, TiCl4,
aldehyde (R-CHO), THF, reflux, 12a (38.2%), 12b (63.9%).
n-BuLi and then reacted with 3-(dimethylamino)-1-(3-fluorophe- 149
nyl) propan-1-one to give compounds 14 in 40.2% yield. 150
Scheme 3. Reagents and conditions: (a) Borane tetrahydrofuran 151
complex, THF, 0 8C to room temperature, 5 h, 93.5%; (d) n-BuLi, 152
À40 8C to room temperature, 3 h, 40.2%.
153
3. Results and discussion
154
All of these synthesized compounds were screened for anti-TB 155
activity. The protocol of the anti-TB activity against M. tuberculosis 156
H37Rv strain with the Microplate Alamar Blue Assay (MABA) was 157
described in previous research [23]. The cytotoxicity against 158
HepG2 cell lines were carried out following the method of 159
literature [24]. All of the compounds were evaluated with the 160
145
2.3. Series 2
146
147
148
Series 2 was synthesized following Scheme 3. Treatment of
9H-thioxanthen-9-one with borane tetrahydrofuran complex
afforded intermediate 13 in 93.5% yield. Activation of 13 with
maximum concentration of 32
studies and cell cytotoxicity were listed in Table 1.
Compound 6e showed the most effective anti-tuberculosis 163
activity with MIC90 value of 4 g/mL against M. tuberculosis H37Rv 164
m
g/mL. The results of anti-TB 161
162
m
strain, which is very impressive to play as a lead compound for 165
further development. Moreover, compound 6e did not show an 166
obvious cytotoxicity at the concentration of 32
mg/mL, which 167
enhances the potential to be further developed. In comparison, 168
other compounds in series 1 with terminal alkyl (6a), hydroxyl (4), 169
carboxyl (2), alkoxy (5) and phenoxy (6b) via an alkyl bridge show 170
no anti-tuberculosis activity. And there were also no obvious 171
Scheme 3. Reagents and conditions: (a) Borane tetrahydrofuran complex, THF, 0 8C
to r.t., 5 h, 93.5%; (d) n-BuLi, À40 8C to r.t., 3 h, 40.2%.
Please cite this article in press as: C.-X. He, et al., Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis
agents, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.03.027

G Model
CCLET 3256 1–4
4
C.-X. He et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
Table 1
Appendix A. Supplementary data
209
Anti-tuberculosis activity and cytotoxicity evaluations of synthesized compounds.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.03.
027.
210
211
212
Compd.
MIC90
(
m
g/mL)
CC50 (mg/mL)
2
>32
>32
>32
>32
>32
31
>32
24
4
5
>32
>32
>32
>32
>32
>32
>32
>32
>32
14
6a
References
213
6b
6c
[1] A. Koul, E. Arnoult, N. Lounis, J. Guillemont, K. Andries, The challenge of new drug
discovery for tuberculosis, Nature 469 (2011) 483–490.
[2] M.D. Iseman, Tuberculosis therapy: past, present and future, Eur. Respir. J. Suppl.
36 (2002) 87s–94s.
[3] WHO publishes Global tuberculosis report 2013, Euro surveillance: bulletin
Europeen sur les maladies transmissibles, Eur. Commun. Dis. Bull. 18 (2013).
[4] C. Nathan, Drug-resistant tuberculosis: a new shot on goal, Nat. Med. 20 (2014)
121–123.
[5] E. Pontali, A. Matteelli, G.B. Migliori, Drug-resistant tuberculosis, Curr. Opin. Pulm.
Med. 19 (2013) 266–272.
[6] N. Motohashi, S.R. Gollapudi, J. Emrani, K.R. Bhattiprolu, Antitumor properties of
phenothiazines, Cancer Invest. 9 (1991) 305–319.
[7] L. Amaral, M. Viveiros, J. Molnar, Antimicrobial activity of phenothiazines, In Vivo
18 (2004) 725–731.
[8] C. Miskolci, I. Labadi, T. Kurihara, N. Motohashi, J. Molnar, Guanine-cytosine rich
regions of plasmid DNA can be the target in anti-plasmid effect of phenothiazines,
Int. J. Antimicrob. Agents 14 (2000) 243–247.
[9] L. Amaral, J.E. Kristiansen, M. Viveiros, J. Atouguia, Activity of phenothiazines
against antibiotic-resistant Mycobacterium tuberculosis: a review supporting fur-
ther studies that may elucidate the potential use of thioridazine as anti-tubercu-
losis therapy, J. Antimicrob. Chemother. 47 (2001) 505–511.
[10] P.B. Madrid, W.E. Polgar, L. Toll, M.J. Tanga, Synthesis and antitubercular activity
of phenothiazines with reduced binding to dopamine and serotonin receptors,
Bioorg. Med. Chem. Lett. 17 (2007) 3014–3017.
[11] L. Amaral, A. Martins, G. Spengler, A. Hunyadi, J. Molnar, The mechanism by which
the phenothiazine thioridazine contributes to cure problematic drug-resistant
forms of pulmonary tuberculosis: recent patents for ‘‘new use’’, Recent Pat
Antiinfective Drug Discov 8 (2013) 206–212.
[12] L. Amaral, M. Martins, M. Viveiros, J. Molnar, J.E. Kristiansen, Promising therapy of
XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps,
Curr. Drug Targets 9 (2008) 816–819.
[13] L.E. Hollister, D.T. Eikenberry, S. Raffel, Chlorpromazine in nonpsychotic patients
with pulmonary tuberculosis, Am. Rev. Respir. Dis. 81 (1960) 562–566.
[14] B. Beckmann, H. Hippius, E. Ruther, Treatment of schizophrenia, Prog. Neurop-
sychopharmacol. 3 (1979) 47–52.
[15] S. Kapur, R.B. Zipursky, G. Remington, Clinical and theoretical implications of
5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in
schizophrenia, Am. J. Psychiatry 156 (1999) 286–293.
[16] P. Ratnakar, S.P. Rao, P. Sriramarao, P.S. Murthy, Structure–antitubercular activity
relationship of phenothiazine-type calmodulin antagonists, Int. Clin. Psychophar-
macol. 10 (1995) 39–43.
[17] D. Addla, A. Jallapally, D. Gurram, P. Yogeeswari, D. Sriram, S. Kantevari, Rational
design, synthesis and antitubercular evaluation of novel 2-(trifluoromethyl)phe-
nothiazine-[1,2,3]triazole hybrids, Bioorg. Med. Chem. Lett. 24 (2014) 233–236.
[18] A.P. Feinberg, S.H. Snyder, Phenothiazine drugs: structure–activity relationships
explained by a conformation that mimics dopamine, Proc. Natl. Acad. Sci. U. S. A.
72 (1975) 1899–1903.
[19] A. Jaszczyszyn, K. Gasiorowski, P. Swiatek, W. Malinka, K. Cieslik-Boczula, J.
Petrus, B. Czarnik-Matusewicz, Chemical structure of phenothiazines and their
biological activity, Pharmacol. Rep. 64 (2012) 16–23.
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
6d
6e
32
4
9a
>32
>32
31
9b
11
12a
12b
14
>32
29
15
7
12
CPZ HCl
22
8
Reference compound Rifampicin: MIC90 = 0.13 mg/mL.
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
improvement on the anti-tuberculosis activity when slightly
modification on the phenothiazine core (9a, 9b, 11, 12a) to
discriminate the conjugation system or replace phenothiazine
with thioxanthenes and 9H-thioxanthene. In addition, the weak
anti-tuberculosis activity of compound 11 and 12b also implicate
that a non-basic aryl substituents at the 10-position of phenothia-
zine ring can also maintain anti-tuberculosis activity. In summary,
compared to the mother drug CPZ, phenothiazine derived
compounds without 2-substituent and with 10-non-basic sub-
stituents can still remain or further increase the anti-TB activity,
such as 6e. Importantly, these modifications are likely to eliminate
the corresponding side effects such as anti-psychotic activity and
EPMS.
In series 2, the representative compound 14 which adopts part
of the moiety from TMC207 exhibits interesting anti-TB activity
(7
mg/mL) as expected. However, compound 14 also show an
obvious cyto-toxicity (Table 1). Thus, further development of this
series of compounds was suspended.
190
4. Conclusion
191
192
193
194
195
196
197
198
199
200
201
202
203
204
Phenothiazine is known for its anti-psychotic pharmacological
efficacy. Interestingly, these phenothiazine derivatives also show
reasonable anti-TB activity but relative weak and with various
psychotic related side effect. In this study, we designed two series
phenothiazine derives compounds, and proved that 2-substituents
and N, N-dimethyl amino terminal of Phenothiazine drugs which
determine the optimal neuroleptic activity is not the essential
elements to maintain the anti-TB activity. Our optimization also
lead compound 6e with increased the anti-TB activity
(MIC90 = 4
pound CPZ (MIC90 = 22
toxic to mammalian cells. Compound 6e has a new structure
moiety different from current known anti-TB drugs and can be
used as the lead for the further development of anti-TB agents.
[20] E. Cox, K. Laessig, FDA approval of bedaquiline – the benefit-risk balance for drug-
resistant tuberculosis, N. Engl. J. Med. 371 (2014) 689–691.
[21] K. Andries, P. Verhasselt, J. Guillemont, H.W. Gohlmann, J.M. Neefs, H. Winkler, J.
Van Gestel, P. Timmerman, M. Zhu, E. Lee, P. Williams, D. de Chaffoy, E. Huitric, S.
Hoffner, E. Cambau, C. Truffot-Pernot, N. Lounis, V. Jarlier, A diarylquinoline drug
active on the ATP synthase of Mycobacterium tuberculosis, Science 307 (2005)
223–227.
[22] D. Cummins, G. Boschloo, M. Ryan, D. Corr, S.N. Rao, D. Fitzmaurice, Ultrafast
electrochromic windows based on redox-chromophore modified nanostructured
semiconducting and conducting films, J. Phys. Chem. B 104 (2000) 11449–11459.
[23] Y. Lu, M. Zheng, B. Wang, L. Fu, W. Zhao, P. Li, J. Xu, H. Zhu, H. Jin, D. Yin, H. Huang,
A.M. Upton, Z. Ma, Clofazimine analogs with efficacy against experimental
tuberculosis and reduced potential for accumulation, Antimicrob. Agents Che-
mother. 55 (2011) 5185–5193.
m
g/mL, CC50 > 32
m
g/mL) compared to mother com-
g/mL), but much less
m
g/mL, CC50 = 8
m
205
Acknowledgment
[24] H. Cui, J. Carrero-Lerida, A.P. Silva, J.L. Whittingham, J.A. Brannigan, L.M. Ruiz-
Perez, K.D. Read, K.S. Wilson, D. Gonzalez-Pacanowska, I.H. Gilbert, Synthesis and
evaluation of alpha-thymidine analogues as novel antimalarials, J. Med. Chem. 55
(2012) 10948–10957.
206 Q3
207
208
We are grateful to ‘‘The National High-Tech Research and
Development Program (‘‘863’’Program) of China’’ (No.
2012AA020302) for financial support.
Please cite this article in press as: C.-X. He, et al., Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis
agents, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.03.027