Diversity-oriented synthesis and activity evaluation of substituted bicyclic lactams as anti-malarial against Plasmodium falciparum.
TL;DR: This study unveils a DOS-mediated exploration of small molecules with novel structural motifs that culminates in identifying a potential lead molecule against malaria.
Abstract: Background: Malaria remains the world’s most important devastating parasitic disease. Of the five species of Plasmodium known to infect and cause human malaria, Plasmodium falciparum is the most virulent and responsible for majority of the deaths caused by this disease. Mainstream drug therapy targets the asexual blood stage of the malaria parasite, as the disease symptoms are mainly associated with this stage. The prevalence of malaria parasite strains resistance to existing anti-malarial drugs has made the control of malaria even more challenging and hence the development of a new class of drugs is inevitable. Methods: Screening against different drug resistant and sensitive strains of P. falciparum was performed for few bicyclic lactam-based motifs, exhibiting a broad spectrum of activity with low toxicity generated via a focussed library obtained from diversity oriented synthesis (DOS). The synthesis and screening was followed by an in vitro assessment of the possible cytotoxic effect of this class of compounds on malaria parasite. Results: The central scaffold a chiral bicyclic lactam (A) and (A’) which were synthesized from (R)-phenylalaninol, levulinic acid and 3-(2-nitrophenyl) levulinic acid respectively. The DOS library was generated from A and from A’, by either direct substitution with o-nitrobenzylbromide at the carbon α- to the amide functionality or by conversion to fused pyrroloquinolines. Upon screening this diverse library for their anti-malarial activity, a dinitro/diamine substituted bicyclic lactam was found to demonstrate exceptional activity of >85% inhibition at 50 μM concentration across different strains of P. falciparum with no toxicity against mammalian cells. Also, loss of mitochondrial membrane potential, mitochondrial functionality and apoptosis was observed in parasite treated with diamine-substituted bicyclic lactams. Conclusions: This study unveils a DOS-mediated exploration of small molecules with novel structural motifs that culminates in identifying a potential lead molecule against malaria. In vitro investigations further reveal their cytocidal effect on malaria parasite growth. It is not the first time that DOS has been used as a strategy to identify therapeutic leads against malaria, but this study establishes the direct implications of DOS in scouting novel motifs with anti-malarial activity.
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TL;DR: Surface-associated TRAP (thrombospondin-related anonymous protein) family proteins are conserved across the phylum of apicomplexan parasites, indicating that motor-binding TRAP family members function not just in parasite motility and cell invasion but also in membrane disruption and cell egress.
56 citations
TL;DR: An (S)‐tryptophanol‐derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite′s life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.
Abstract: Malaria continues to be a major cause of morbidity and mortality to this day, and resistance to drugs like chloroquine has led to an urgent need to discover novel chemical entities aimed at new targets. Here, we report the discovery of a novel class of potential antimalarial compounds containing an indolizinoindolone scaffold. These novel enantiopure indolizinoindolones were synthesized, in good-to-excellent yields and excellent diastereoselectivities, by cyclocondensation reaction of (S)- or (R)-tryptophanol and 2-acyl benzoic acids, followed by intramolecular α-amidoalkylation. Interestingly, we were able to synthesize for the first time 7,13b-cis indolizinoindolones in a two-step route. The novel compounds showed promising activity against erythrocytic stages of the human malaria parasite, Plasmodium falciparum, and liver stages of the rodent parasite Plasmodium berghei. In particular, an (S)-tryptophanol-derived isoindolinone was identified as a promising starting scaffold to search for novel antimalarials, combining excellent activity against both stages of the parasite's life cycle with low cytotoxicity and excellent metabolic and chemical stability in vitro.
27 citations
TL;DR: It is shown that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation.
Abstract: Natural products offer an abundant source of diverse novel scaffolds that inspires development of next generation anti-malarials. With this vision, a library of scaffolds inspired by natural biologically active alkaloids was synthesized from chiral bicyclic lactams with steps/scaffold ratio of 1.7:1. On evaluation of library of scaffolds for their growth inhibitory effect against malaria parasite we found one scaffold with IC50 in low micro molar range. It inhibited parasite growth via disruption of Na+ homeostasis. P-type ATPase, PfATP4 is responsible for maintaining parasite Na+ homeostasis and is a good target for anti-malarials. Molecular docking with our scaffold showed that it fits well in the binding pocket of PfATP4. Moreover, inhibition of Na+-dependent ATPase activity by our potent scaffold suggests that it targets parasite by inhibiting PfATP4, leading to ionic imbalance. However how ionic imbalance attributes to parasite's death is unclear. We show that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation. Our study provides a novel strategy for drug discovery and an insight into the molecular mechanism of ionic imbalance mediated death in malaria parasite.
18 citations
TL;DR: Interestingly, the benzoxazine derivatives of eugenol with GO nanoparticle exhibited enhanced therapeutic potential in cancer cells and significant role of these derivatives on parasite suggesting its multi-pharmacological capability.
Abstract: Natural products from medicinal plants have always attracted a lot of attention due to their diverse and interesting therapeutic properties. We have employed the principles of green chemistry involving isomerization, coupling and condensation reaction to synthesize a class of compounds derived from eugenol, a naturally occurring bioactive phytophenol. The compounds were characterized structurally by 1H-, 13C-NMR, FT-IR spectroscopy and mass spectrometry analysis. The purity of compounds was detected by HPLC. The synthesized compounds exhibited anti-cancer activity. A 10–12-fold enhancement in efficiency of drug molecules (~ 1 µM) was observed when delivered with graphene oxide (GO) as a nanovehicle. Our data suggest cell death via apoptosis in a dose-dependent manner due to increase in calcium levels in specific cancer cell lines. Interestingly, the benzoxazine derivatives of eugenol with GO nanoparticle exhibited enhanced therapeutic potential in cancer cells. In addition to anti-cancer effect, we also observed significant role of these derivatives on parasite suggesting its multi-pharmacological capability.
14 citations
TL;DR: Levulinic acid (LEV) has been identified as a key building block chemical produced entirely from biomass and its derivatives can be used to synthesize a variety of value-added chemicals, such as 2-but...
Abstract: Levulinic acid (LEV) has been identified as a key building block chemical produced entirely from biomass. Its derivatives can be used to synthesize a variety of value-added chemicals, such as 2-but...
5 citations
References
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TL;DR: The present review article focuses on the pharmacological profile of 2-azetidinones with their potential activities.
168 citations
"Diversity-oriented synthesis and ac..." refers background in this paper
...Biologically active lactams range from β-lactams, used in diverse therapeutic areas viz serine-dependent enzyme inhibitors, matrix-metalloprotease inhibitors, and even apoptosis inductors [22,23], the inhibition of HIV-1 protease, antitumor activity, anti-malarial activity, and cholesterol absorption inhibition [24-30], peptides, bicyclic lactams (as potential anticancer and anti-malarials) etc....
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TL;DR: Three clones have been prepared from the Honduras I/CDC strain of Plasmodium falciparum by a method of microscopic selection, and all three are as resistant to pyrimethamine as the original line, andall three form knobs on the erythrocyte surface.
Abstract: Three clones have been prepared from the Honduras I/CDC strain of Plasmodium falciparum by a method of microscopic selection. One of these (HB-2) does not form gametocytes whereas the others (HB-1 and HB-3) do. All three are as resistant to pyrimethamine as the original line, and all three form knobs on the erythrocyte surface.
136 citations
"Diversity-oriented synthesis and ac..." refers methods in this paper
...Compound D exhibited the 77.84 and 79.34% of inhibition in drug-sensitive clones 3D7 and HB3, respectively, whereas 59.3% in drug-resistant clone Dd2 at 50 μM of concentration (Figure 3A,B)....
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...Plasmodium falciparum clones used in this study 3D7, Dd2 and HB3 [12-14], were cultured in O+ human erythrocytes supplemented with RPMI 1640 (Invitrogen, USA) 24 mM sodium bicarbonate (Sigma, USA), 0.1 mM hypoxanthine (Invitrogen, USA), 25 mg/ml gentamicin (Invitrogen, USA) and 0.5% AlbuMax I (Invitrogen, USA), according to methods described earlier [15]....
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...Upon testing this focused library for their anti-malarial activity, dinitro/diamine substituted bicyclic lactams were found most effective growth inhibitory compound against both drug-resistant clone Dd2 and drug-sensitive clones HB3 and 3D7 of P. falciparum....
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...Compound C exhibited the 48.6 and 39.9% of inhibition in drug-sensitive clones HB3 and 3D7, respectively, whereas 34.24% in drug-resistant clone Dd2 at 10 μM of concentration; also at 50 μM of concentration, it showed 85.27 and 88.35% of inhibition in drug-sensitive clones 3D7 and HB3, respectively, whereas 67.27% in drugresistant clone Dd2....
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...(A) Bar graph showing the growth-inhibitory effect of dintro-substituted compound C at 50 μM concentration on sorbitol synchronized P. falciparum drug-sensitive clones 3D7, HB3 and drug-resistant clones Dd2....
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TL;DR: Compounds of a combinatorial monocyclic beta-lactam library were found to be apparently uncompetitive inhibitors of HIV-1 protease, providing lead compounds for a new class of HIV protease inhibitors.
134 citations
"Diversity-oriented synthesis and ac..." refers background in this paper
...Biologically active lactams range from β-lactams, used in diverse therapeutic areas viz serine-dependent enzyme inhibitors, matrix-metalloprotease inhibitors, and even apoptosis inductors [22,23], the inhibition of HIV-1 protease, antitumor activity, anti-malarial activity, and cholesterol absorption inhibition [24-30], peptides, bicyclic lactams (as potential anticancer and anti-malarials) etc....
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01 Mar 1999
128 citations
TL;DR: This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin-based combinations to those that need them most.
Abstract: SUMMARY The emergence and spread of drug-resistant malaria parasites is the major
threat to effective malaria control. So far, malaria control has relied
heavily on a restricted number of chemically related drugs belonging to either
the quinoline or the antifolate groups. Only recently have the
artemisinin-type compounds been used widely, predominantly in Southeast Asia.
Experience has shown that resistance eventually curtails the life span of
antimalarial drugs. If measures are not applied to contain resistance, the
investment put into the development of new drugs will be squandered. Current efforts focus, on the one hand, on research into novel compounds
with mechanisms of action that are different to the traditionally used drugs,
and, on the other hand, on measures to prevent or delay resistance when drugs
are introduced. Drug discovery and development are long, risky and expensive
ventures. Whilst very few new antimalarial drugs were developed in the last
quarter of the 20th century (only four of the nearly 1400 drugs registered
worldwide during 1975-1999), various private and public institutions are at
work to discover and develop new compounds. Today, the antimalarial pipeline
is relatively healthy. Projects are underway at different stages of drug
development, from pre-development to registration. However, there is
relatively little novelty, as current development projects still rely upon the
traditional quinoline, antifolate and, in particular, artemisinin compounds.
New structures are expected from the more upstream discovery efforts but it
will take time before they become drugs. Therefore, whilst waiting for the drugs of tomorrow, there is a pressing
need for immediately available, effective and affordable drugs that will have
long life spans. Drug combinations that have independent modes of action are
seen as a way of enhancing efficacy while ensuring mutual protection against
resistance. Most research work has focussed on the use of artesunate combined with
currently used standard drugs, namely mefloquine, amodiaquine,
sulfadoxine/pyrimethamine and chloroquine. There is clear evidence that
combinations improve efficacy without increasing toxicity. However, the
absolute cure rates that are achieved by combinations vary widely and are
dependent on the level of resistance of the standard drug. From these studies,
further work is underway to produce fixed dose combinations that will be
packaged in blister packs. Malaria control programmes need efficacious drugs
that can be used with ease by the populations of endemic countries. This review will summarise current antimalarial drug developments and
outline recent clinical research that aims to bring artemisinin-based
combinations to those that need them most.
122 citations
"Diversity-oriented synthesis and ac..." refers background in this paper
...Of the nearly 1,400 drugs registered worldwide in the last quarter of the 20th Century, only four were anti-malarials [3]....
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