Bioorganic & Medicinal Chemistry Letters
Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)
rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis
Zmp1
Mattia Mori a,b, Davide Deodato a, Mohan Kasula a, Davide M. Ferraris c, Adriana Sanna d,
Alessandro De Logu e, Menico Rizzi c, Maurizio Botta a,f,
⇑
a Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, Italy
b Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, viale Regina Elena 291, 00161 Roma, Italy
c DiSF-Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy
d Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy
e Department of Life and Enviromental Sciences, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy
f Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333,
1900 N 12th Street, Philadelphia, PA 19122, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed,
synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost
all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC50 values in the range 1.3–43.9
mM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7 mM,
respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to
highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4
and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration
of 10 mg/ml. This work represents a step forward in targeting Zmp1 by small molecules.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 30 November 2017
Revised 16 January 2018
Accepted 17 January 2018
Available online xxxx
Keywords:
Rhodanines
Aminothiazoles
Zmp1
Tuberculosis
Metalloproteases
Tuberculosis (TB) is an infectious disease caused by Mycobac-
terium tuberculosis (Mtb) that has been one of the top ten causes
of death worldwide in 2015.1 To control TB spread, in the ’90s
the WHO has launched the DOTS (Directly Observed Treatment,
Short Course) strategy that proved successful in effectively achiev-
ing cure rates over 90% in countries where the health system works
well. On the contrary, DOTS proved notably less successful in cases
of HIV co-infections or in patients infected by multidrug-resistant
(MDR), extensively drug-resistant (XDR) and totally drug-resistant
(TDR) Mtb strains.2–4 Therefore, novel and effective strategies to
treat and control TB are still urgently needed, and may be achieved
by targeting Mtb validated targets or Mtb proteins that are rele-
vant for its replication and survival into the host.5–7 In this context,
Mtb-secreted extracellular proteins are attracting much interest
either as candidate drug targets or biomarkers of active and latent
TB, mostly because of their predominant role in virulence, in medi-
ating host-pathogen interaction, and in attenuating host immune
response.8–10 Among them, the extracellular zinc metalloprotease
1 (Zmp1)11–13 has been reported to play a key role in phagosome
maturation and to elicit TB-specific humoral immune response,14
thus enhancing the overall survival of Mtb in the host. In a guinea
pig model of TB infection, Zmp1 deletion has led to increase the
protective efficacy of the live vaccine Mycobacterium bovis BCG,12
in agreement with Master et al.,15 showing that Zmp1 deletion is
associated to virulence attenuation. In contrast, Muttucumaru
et al. have showed that deletion of the Zmp1 gene leads to bacterial
hypervirulence in a murine model.16 Nevertheless, it is clear from
multiple reports that Zmp1 plays a relevant role in host–pathogen
interaction, and that the design of specific small molecule inhibi-
tors could be a valuable strategy towards anti-TB therapeutics.
Zmp1 inhibitors may also serve as tools to further understanding
the pathogenic role of Zmp1.
Based on the available X-ray structure of Zmp1/ligand com-
plex,17 we recently identified the 3-(carboxymethyl)rhodanine as
privileged scaffold of Zmp1 inhibitors by disclosing ZTB23(R),
ZTB28(R) and ZTB29(R) (Fig. 1) as confirmed hits.18 Subsequent
⇑
Corresponding author at: Department of Biotechnology, Chemistry and Phar-
macy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.