Bioorganic & Medicinal Chemistry
A trio of quinoline-isoniazid-phthalimide with promising antiplasmodial
potential: Synthesis, in-vitro evaluation and heme-polymerization
inhibition studies
,
*
Anu Rania, Anny Sharmaa, Jenny Legacb, Philip J. Rosenthalb, Parvesh Singhc, Vipan Kumara
a Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, Punjab, India
b Department of Medicine, University of California, San Francisco, CA, USA
c School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban, South Africa
A R T I C L E I N F O
A B S T R A C T
Keywords:
Quinoline-isoniazid-phthalimide triads have been synthesised to assess their antiplasmodial efficacy and cyto-
toxicity against chloroquine-resistant W2 strain of P. falciparum and Vero cells, respectively. Most of the syn-
thesized compounds displayed IC50 in lower nM range and appeared to be approximately five to twelve fold more
active than chloroquine. Heme-binding studies were also carried out to delineate the mode of action. The
promising compounds with IC50s in range of 11–30 nM and selectivity index >2800, may act as promising
template for the design of new antiplasmodials.
Quinoline-isoniazid-phthalimide triads
Antiplasmodial
Cytotoxicity
Heme-binding studies
1. Introduction
resistance.11–13
In the development of antimalarial therapy, quinoline-core has
Malaria continues to be a public health challenge worldwide. Plas-
modium falciparum is the most fatal and contributory species responsible
for highest malaria morbidity and is responsible for half a million deaths
every year.1 WHO world malaria report-2019 estimated 228 million
malaria cases and 405,000 malaria related deaths in 2018, which is an
increase of ~9 million cases compared to the previous year. These
numbers confirm that malaria is still one of the world’s most lethal
parasitic infection. Around two-thirds of the affected population glob-
ally are infants under the age of five and expectant mothers.2 The
currently available anti-malarial drugs invariably suffer from lower
effectiveness, and development of resistant parasitic strains thus
limiting their therapeutic efficacy.3 Most of the previously used anti-
malarial treatments such as quinine, chloroquine, mefloquine, amodia-
quine, piperaquine, sulfadoxine-pyrimethamine and halofantrine, suf-
fered from the above mentioned problems.1,4 Among the currently
employed antimalarials, artemisinin combination therapies (ACTs)
proved to be the most effective, especially against P. falciparum.5–8
However, no present-day first line antimalarial match the favorable ef-
ficacy, safety, and affordability once held by CQ.9,10 The increasing
malaria related morbidity/mortality along with the lack of a suitable
vaccine, therefore provide a strong impetus for the identification and
development of new therapeutic frameworks with low incidence of
played a prominent role as shown by drugs like quinine, chloroquine,
mefloquine, amodiaquine, primaquine, piperaquine and while few
scaffolds are under clinical trials (Fig. 1).14 4-aminoquinoline-hybridiza-
tion involving the fusion of various pharmacophores with 4-aminoqui-
noline core is considered as one of the novel approaches for affording
new molecular structures with promising anti-plasmodial potential.15–18
Iron (Fe) is considered as crucial for cellular proliferation, and Fe-
chelators are known to inhibit the growth of the malarial parasite in
cell culture, in animal and human studies.19 A number of heterocyclic
scaffolds, including the pyridine core act as iron chelators and display
promising antimalarial activities (Fig. 2). 4-isonicotinic hydrazide
(isoniazid), a pyridine analogue is a first line drug in treatment of
tuberculosis (TB). It is an enoyl-ACP reductase inhibitor, an important
enzyme in the biosynthesis of fatty acids (Fig. 2).20
Phthalimide-based moieties have recently gained medicinal chem-
ists’ attention to afford antitumor, antitubercular, antimalarial, anti-
oxidant, anti-microbial, and anti-inflammatory drug candidates.21
Recently, we have disclosed the anti-plasmodial potential of 4-amino-
quinoline linked functionalized phthalimides, with the compounds
exhibiting promising activities in nanomolar range against chloroquine-
resistant (CQR) W2 strain of P. falciparum (Fig. 3).22 In continuation,23
the present paper is a logical extension and includes the synthesis and
* Corresponding author.
Received 31 December 2020; Received in revised form 31 March 2021; Accepted 6 April 2021
Available online 18 April 2021
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