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MedChemComm
DOI: 10.1039/C7MD00146K
Benzylsulfanyl benzo-heterocycle amides and hydrazones as new
agents against drug susceptible and resistant Mycobacterium tubercu-
†
losis
a,b
a
c
c
c
d
Xiaoyun Lu *, Xianglong Hu , Zhiyong Liu , Tianyu Zhang , Ruibing Wang , Baojie Wan , Scott G.
d
b
Franzblau , Qidong You *
a
School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing210009, China
b
c
Tuberculosis Research Laboratory, State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chiꢀ
nese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China
d
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612,
USA
Corresponding Author:* (X. L.) Email: luxy2016@jnu.edu.cn, phone: +86ꢀ20ꢀ85221523; Fax: +86ꢀ20ꢀ85224766;* (Q. D.) Email:
youqd@163.com. phone: +86ꢀ25ꢀ83271351; Fax: +86ꢀ25ꢀ83271351.
†
The authors declare no competing interests.
ABSTRACT: A series of benzylsulfanyl benzoꢀheterocycle amides and hydrazones were synthesized and evaluated for antiꢀtubercular
activities. The isonicotinyl hydrazones derivatives 12d, 12e and 12f exhibited good antiꢀtubercular activity against Mycobacterium tuber-
culosis H Rv (ATCC # 27294) with MIC values of 0.23, 0.24 and 0.24 ꢁM, respectively, and were also active against SDRꢀTB, MDRꢀTB
37
and XDRꢀTB. More importantly, compound 12e also showed low cytotoxicity, good metabolic stability, and could significantly reduce the
mycobacterial burden in a mouse model infected with autoluminescent H37Ra strain, which may serve as a lead compound for further
development.
KEYWORDS: Benzylsulfanyl benzoꢀheterocycle amides and hydrazones, Drug resistant, MDRꢀTB, Molecular hybridization, Antiꢀ
tubercular
1
.
Introduction
Tuberculosis (TB), a highly contagious and airꢀborne disease
caused by Mycobacterium tuberculosis (Mtb), emerged with mulꢀ
tiꢀdrug resistant (MDRꢀTB), extensively drugꢀresistant (XDRꢀTB)
strains and acquired immune deficiency syndrome (AIDS) in
1
recent years. The World Health Organization (WHO) 2016
“
Global Tuberculosis Report” estimated that nearly 1.8 million
people died from TB and 10.4 million new TB cases were notified
2
to national authorities in 2015. In spite of the increasing worldꢀ
wide incidence of TB, only bedaquiline (SIRTURO®) and
3ꢀ4
delamanid were conditionally approved by FDA in 2012
and
EMEA in 2014 for treatment of MDRꢀTB, respectively. However,
bedaquiline possessed serious adverse effects such as cardiac
arrhythmias and displayed higher death rates than that of the plaꢀ
5
cebo group in a clinical investigation, which limited its wide
application in clinical practice. Therefore, it is an imperative need
to develop novel antiꢀtubercular drugs that can be equally effecꢀ
tive against Mtb and MDRꢀTB without any toxic side effects, and
also can reduce the duration of therapy.
Fig. 1 The design of antiꢀtubercular compounds by molecular
hybridization.
2
.
Results and discussion
To pursue this goal, our research efforts were directed to disꢀ
cover new chemical classes of antiꢀtubercular agents. It was indiꢀ
cated that the benzylsulfanyl derivatives of benzoxaꢀ
zole/benzothiazole/benzimidazole have significant antimycobacteꢀ
Two series of benzylsulfanyl benzoꢀheterocycle amides and
hydrazones derivatives are shown in Table 1, and the synthetic
procedures used for their preparation are demonstrated in
Schemes 1ꢀ2. In Scheme 1, synthesis of compounds 7aꢀ7f started
from preparation of 4ꢀ(bromomethyl) benzonitrile 2 by brominaꢀ
tion of αꢀH in 4ꢀmethylbenzonitrile 1 using KBrO /NaHSO as
6ꢀ7
rial activity. Additionally, some scientists carried out on pyraꢀ
zinecarboxamides derivatives and hydrazones of isoniazid as antiꢀ
3
3
8ꢀ9
tubercular pharmacophores to reduce the toxicity of isoniazid.
bromination agents and under an incandescent light illumination.
Mercaptomethyl benzonitrile benzoꢀheterocycle derivatives 4aꢀ4c
were prepared by nucleophilic substitution reaction in N, Nꢀ
dimethylformamide (DMF) in the presence of potassium carꢀ
bonate at 20 °C or sodium methoxide at room temperature. Reꢀ
duction of 4aꢀ4c with lithium aluminium hydride in dry THF gave
the mercaptomethyl aniline benzoꢀheterocycle derivatives 5aꢀ5c.
Condensation derivatives 5aꢀ5c with pyridine carboxylic acid 6
gave the desired amide analogues 7aꢀ7f, respectively.
Under these medicinal chemistry advances, two novel classes of
benzylsulfanyl benzoꢀheterocycle amides 7aꢀ7f and hydrazones
1
2aꢀ12f were designed by molecular hybridization between
pyridyl amide or hydrazone and benzylsulfanyl benzoꢀheterocycle,
respectively. Some of them showed good antiꢀtubercular activity
against H37Rv, singleꢀdrug resistant strains (SDRꢀTB), MDRꢀTB
and XDRꢀTB in vitro. Here, we report the synthesis and evaluaꢀ
tion of benzylsulfanyl benzoꢀheterocycle amides and hydrazones
derivatives as novel antiꢀtubercular agents.
The benzylsulfanyl benzoꢀheterocycle hydrazone derivatives
1
2aꢀ12f were synthesized as shown in Scheme 2. Selectivity sinꢀ