Bioorganic & Medicinal Chemistry Letters 14 (2004) 3923–3924
Antituberculous activity of some aryl semicarbazone derivatives
Dharmarajan Sriram,* Perumal Yogeeswari and Rathinasabapathy Thirumurugan
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India
Received 7 April 2004; revised 21 May 2004; accepted 24 May 2004
Available online
Abstract—During the course of our work on the synthesis and screening of new drugs for tuberculosis, we have identified N1-(4-
acetamido phenyl)-N4-(2-nitro benzylidene) semicarbazone (1b), which inhibited in vitro Mycobacterium tuberculosis H37Rv; 100%
inhibition at 1.56 lg/mL. This paper is first of its kind in which aryl semicarbazones are reported to possess antimycobacterials
potency greater than p-aminosalicylic acid, ethionamide, ethambutol, ciprofloxacin and kanamycin.
Ó 2004 Published by Elsevier Ltd.
1. Introduction
2. Chemistry
Tuberculosis (TB) is one of the most common infectious
diseases known to man. About 32% of the world’s
population (1.86 billion people) is infected with TB.
Every year, approximately 8 millions of these infected
people develop active TB, and almost 2millions of these
would die from the diseases.1 The incidence of TB
infection has steadily risen in the last decade and this
increase can be attributed to a similar increase in human
immunodeficiency virus (HIV) infection.2 The associa-
tion of TB and HIV infections is so dramatic that, in
some cases, nearly two-thirds of the patients diagnosed
with TB are also HIV-1 seropositive.3 Furthermore,
numerous studies have shown that TB is a cofactor in
the progression of HIV infection.4 The reemergence of
TB infection is further complicated by an increase in
cases, which are resistant to conventional antitubercular
drug therapy. The increasing rate of multi drug resistant
TB does not only create problems for the treatment, but
also the costs are exploding. Thus, new drugs are nec-
essary to overcome the current problems of therapy. In
the course of screening to discover new compounds
employed in the chemotherapy of tuberculosis, we
identified semicarbazones derivatives, which inhibited
in vitro Mycobacterium tuberculosis H37Rv. We present
preliminary results concerning the synthesis and the
initial in vitro antituberculous activity of first represen-
tative compound of this family.
The synthesis of various phenyl semicarbazones was
achieved by the method described previously.5 Appro-
priately substituted aniline was treated with sodium
cyanate in the presence of glacial acetic acid to yield
appropriate phenyl urea. The urea derivative on con-
densation with hydrazine hydrate in ethanol in the
presence of sodium hydroxide gave the appropriate
phenyl semicarbazide. The semicarbazones (1a–1e, 2a–
2e) were prepared by reaction of the appropriate alde-
hyde with appropriate phenyl semicarbazide (Scheme 1).
The compounds of this study were identified by spectral
data. In general, IR spectra showed the C@N peak at
1610–1590 cmÀ1 and the NH stretching vibrations at
3450 cmÀ1. The semicarbazone derivatives exhibited
characteristic amide bonds at 3300–3240 cmÀ1 and
1700–1670 cmÀ1 and absorption band at 820 cmÀ1 was
characteristic of a substituted phenyl ring. The 1H NMR
spectrum revealed that the hydrazine (@NNH) proton
attached to the phenyl ring at 8.75–9.6 and the aryl NH
proton that showed a singlet at 5.7–6.9 were D2O
exchangeable.
3. Antimycobacterial activity
Primary screening was conducted at 6.25 lg/mL against
M. tuberculosis strain H37Rv (ATCC 27294) in
BACTEC 12B medium using a broth microdilution
assay, the microplate alamar blue assay (MABA).6 The
preliminary results are summarized along with the data
for standard drugs such as isoniazid, ethionamide,
Keywords: Antitubercular; Aryl semicarbazones.
* Corresponding author. Tel.: +91-1596-244684; fax: +91-1596-2441-
0960-894X/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2004.05.060