Bioorganic & Medicinal Chemistry Letters 17 (2007) 1888–1891
N-Hydroxythiosemicarbazones: Synthesis
and in vitro antitubercular activity
Dharmarajan Sriram,* Perumal Yogeeswari, Prathiba Dhakla,
Palaniappan Senthilkumar and Debjani Banerjee
Medicinal Chemistry Research Laboratory, Pharmacy group, Birla Institute of Technology and Science, Pilani 333031, India
Received 3 November 2006; revised 22 December 2006; accepted 11 January 2007
Available online 24 January 2007
Abstract—N-Hydroxythiosemicarbazide was prepared by two methods starting from 2,4-dimethoxy benzyl amine and hydroxyl-
amine hydrochloride, which in turn was reacted with various aldehydes and ketones to obtain the titled compounds. Eighteen com-
pounds were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv using the agar dilution method. Compound
10p was found to be the most potent compound (MIC: 0.28 lM) and was 2.5 times more active than standard isoniazid.
Ó 2007 Elsevier Ltd. All rights reserved.
Tuberculosis (TB) is one of the leading causes of death
due to a single infectious organism in the world.
Approximately one-third of the world’s population has
been infected with the causative organism Mycobacterium
tuberculosis (MTB), eight million become sick with TB
every year, and globally it accounts for almost three mil-
lion deaths annually.1 One-fifth of all deaths of adults in
developing countries are due to TB, which is a re-emer-
gent problem particularly in many industrialized coun-
tries. It was reported that around 19–43% of the
world’s population might get infected with MTB be-
tween 2000 and 2020 if control measures are not
strengthened further.2 The increase of TB during recent
years was largely due to HIV-1 infection, immigration,
increased trade, and globalization.3 Moreover, the
increasing emergence of a drug resistant TB, especially
multidrug resistant-TB (MDR-TB), is particularly
alarming. Multidrug resistant (MDR)-TB has already
caused several fatal outbreaks4 and poses a significant
threat to the treatment and control of the disease in
some parts of the world, where the incidence of MDR-
TB can be as high as 14%.3 As a consequence, without
more effective treatments, the number of infections
caused by MDR-TB will probably increase out of con-
trol. Therefore, the development of new antimicrobial
drugs with potent anti-TB activity is urgently needed.5
However, in the last 40 years, only a few drugs have
been approved by the Food and Drug Administration
(FDA) to treat TB, reflecting the inherent difficulties
in discovery and clinical testing of new agents and the
lack of pharmaceutical industry research in the area.6
In particular, in addition to the current drugs approved
by the FDA for the treatment of TB and the drugs that
commonly are recommended for the treatment of TB
but are not FDA approved,7 a variety of other com-
pounds or classes of compounds are under investigation
as potential antimycobacterial drugs. Among them, thi-
osemicarbazone derivatives were reported by us and
other groups8–10 as antimycobacterial agents. Com-
pound (4-bromophenyl)(phenyl)methanone N-(5-cyc-
lobutyl-1,3-oxazol-2-yl)thiosemicarbazone was found
to be the most active compound in vitro with MIC of
0.05 lg/mL against MTB and MDR-TB, and was 31
times more potent against MDR-TB when compared
to the standard drug INH.8 In continuation of our work
on antimycobacterial thiosemicarbazones, herewith we
are reporting synthesis and antimycobacterial evalua-
tion of newer N-hydroxythiosemicarbazones.
N-Hydroxythiosemicarbazide was prepared by two
methods (Scheme 1), in the first method 2,4-dimethoxy
benzyl amine (1) was condensed with 1,1-thiocarbonyl
diimidazole (2) in dry methanol to furnish the thiocar-
bonyl derivative (3). Further reaction with hydroxyl-
amine hydrochloride (4) in 75% aqueous methanol
Keywords: Thiosemicarbazones; Antimycobacterial activity.
*
Corresponding author. Tel.: +91 1596 244684; fax: +91 1596
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.01.037