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.
Citations
More filters
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
More filters
TL;DR: A series of novel 1,4-diaryl-2-azetidinones prepared by stereospecific Staudinger reaction as conformationally restricted analogues of combretastatin A-4 were evaluated for cytotoxicity against a number of human tumor and normal cell lines.
67 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....
[...]
TL;DR: The compounds MNR4 and MNR5 were found to have highest potency against Plasmodium falciparum in vitro.
57 citations
TL;DR: Interestingly, some compounds demonstrated similar activity against methicillin-susceptible and -resistant strains of Staphylococcus aureus suggesting possible alternative mechanisms of action of these agents, supported by citotoxicity and preliminary scanning electron microscopy studies.
Abstract: The design, synthesis, and antibacterial activity of 4-alkyliden-azetidin-2-ones as new antimicrobial agents against multidrug-resistant pathogens is reported. 4-Alkyliden-azetidin-2-ones were easily obtained using an original protocol starting from 4-acetoxy-azetidinones and diazoesters. Parent compounds were further elaborated to obtain a small library of 4-alkylidene derivatives. A molecular modeling approach using GRID descriptors based on the concept of VRS identified attractive drug candidates and contributed to the rationalization of functional group effects in QSARs. The in vitro antibacterial activity of the new agents was evaluated against 43 recent clinical isolates of antibiotic-susceptible and -resistant Gram-positive and Gram-negative pathogens by determining their minimum inhibitory concentrations (MICs). The most active compound showed MIC values ranging from 0.25 to 32 mg/L against some of the bacterial species tested. Interestingly, some compounds demonstrated similar activity against methicillin-susceptible and -resistant strains of Staphylococcus aureus suggesting possible alternative mechanisms of action of these agents, supported by citotoxicity and preliminary scanning electron microscopy studies.
57 citations
"Diversity-oriented synthesis and ac..." refers background in this paper
...No promising and efficient anti-malarial vaccine is available despite various vaccines being produced and tested [4,5]....
[...]
TL;DR: The role of intracellular Ca2+ in regulation of egress of P. falciparum merozoites from schizonts is tested and novel targets for development of drugs that block egress and limit parasite growth are identified.
Abstract: Egress of Plasmodium falciparum merozoites from host erythrocytes is a critical step in multiplication of blood-stage parasites. A cascade of proteolytic events plays a major role in degradation of membranes leading to egress of merozoites. However, the signals that regulate the temporal activation and/or secretion of proteases upon maturation of merozoites in intra-erythrocytic schizonts remain unclear. Here, we have tested the role of intracellular Ca(2+) in regulation of egress of P. falciparum merozoites from schizonts. A sharp rise in intracellular Ca(2+) just before egress, observed by time-lapse video microscopy, suggested a role for intracellular Ca(2+) in this process. Chelation of intracellular Ca(2+) with chelators such as BAPTA-AM or inhibition of Ca(2+) release from intracellular stores with a phospholipase C (PLC) inhibitor blocks merozoite egress. Interestingly, chelation of intracellular Ca(2+) in schizonts was also found to block the discharge of a key protease PfSUB1 (subtilisin-like protease 1) from exonemes of P. falciparum merozoites to parasitophorous vacuole (PV). This leads to inhibition of processing of PfSERA5 (serine repeat antigen 5) and a block in parasitophorous vacuolar membrane (PVM) rupture and merozoite egress. A complete understanding of the steps regulating egress of P. falciparum merozoites may provide novel targets for development of drugs that block egress and limit parasite growth.
56 citations
"Diversity-oriented synthesis and ac..." refers methods in this paper
...The cells were washed with PBS, and analysed by flow cytometry on FACSCalibur (Becton Dickinson) using CellQuest software [16]....
[...]
TL;DR: This narrative review provides an overview of the state-of-art antimalarial drug therapy, highlights the global portfolio of current Phase III/IV clinical trials and summarizes current developments.
Abstract: Introduction: Chemotherapy of malaria has become a rapidly changing field. Less than two decades ago, treatment regimens were increasingly bound to fail due to emerging drug resistance against 4-aminoquinolines and sulfa compounds. By now, artemisinin-based combination therapies (ACTs) constitute the standard of care for uncomplicated falciparum malaria and are increasingly also taken into consideration for the treatment of non-falciparum malaria.Areas covered: This narrative review provides an overview of the state-of-art antimalarial drug therapy, highlights the global portfolio of current Phase III/IV clinical trials and summarizes current developments.Expert opinion: Malaria chemotherapy remains a dynamic field, with novel drugs and drug combinations continuing to emerge in order to outpace the development of large-scale drug resistance against the currently most important drug class, the artemisinin derivatives. More randomized controlled studies are urgently needed especially for the treatment of ma...
56 citations