Are Antimalarial Hybrid Molecules a Close Reality or a Distant Dream?

Emergence of drug-resistant Plasmodium falciparum strains has led to a situation of haste in the scientific and pharmaceutical communities. Hence, all their efforts are redirected toward finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. In light of this situation, scientists have come up with the concept of hybridization of two or more active pharmacophores into a single chemical entity, resulting in "antimalarial hybrids." The approach has been applied widely for generation of lead compounds against deadly diseases such as cancer and AIDS, with a proven potential for use as novel drugs, but is comparatively new in the sphere of antimalarial drug discovery. A sudden surge has been evidenced in the number of studies on the design and synthesis of hybrids for treating malaria and may be regarded as proof of their potential advantages over artemisinin-based combination therapy (ACT). However, it is evident from recent studies that most of the potential advantages of antimalarial hybrids, such as lower toxicity, better pharmacokinetics, and easier formulation, have yet to be realized. A number of questions left unaddressed at present need to be answered before this approach can progress to the late stages of clinical development and prove their worth in the clinic. To the best of our knowledge, this compilation is the first attempt to shed light on the shortcomings that are surfacing as more and more studies on molecular hybridization of the active pharmacophores of known antimalarials are being published.

In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model.

BACKGROUND: Emergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT). METHODS: Fluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters' four-day suppressive test. RESULTS: Promising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW). CONCLUSIONS: In vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.

Synthesis and antimalarial activity of 7-chloroquinoline-tethered sulfonamides and their [1,2,3]-triazole hybrids.

Aim & background: Drugs with multiple bioactive moieties have the advantages of multiple modes of action and fewer chances of drug resistance. In continuation of our previous work of developing hybrid antimalarials, we present herein the synthesis and antimalarial activity of two different series of 7-chloroquinoline-sulfonamide hybrids. Materials & methods: The first series of compounds were synthesized by using p-dodecylbenzenesulfonic acid as a Bronsted acid catalyst in ethanol. The second series' compounds were synthesized by 1,3-dipolar cycloaddition of azides and alkynes under click reaction conditions. Results & conclusion: The majority of these compounds demonstrated noncytotoxicity and significant antimalarial activity against Plasmodium falciparum (3D7) with IC50 values in the range of 1.49-13.49 µM. The most promising hybrids (12d, 13a and 13c) may be good starting points for next-generation antimalarials.

N-sulfonylpiperidinedispiro-1,2,4,5-tetraoxanes exhibit potent in vitro antiplasmodial activity and in vivo efficacy in mice infected with P. berghei ANKA.

The artemisinin resistance has posed a serious threat against malaria elimination lately. Past few years have seen important development of several peroxide based medicinal compounds and their derivatives such as trioxanes and tetraoxanes. Here, we report a rapid, one-pot method for synthesizing a new series of N-sulfonylpiperidine dispiro-1,2,4,5-tetraoxane analogs with diverse substitution on the tetraoxane ring i.e., various substituted alkyl and aryl sulfonyl chlorides, as well as cyclic, acyclic and aryl substituted ketones. All the synthesized tetraoxanes were characterized by spectroscopic (1H NMR,13C NMR), and spectrometric (High-resolution mass spectrometry) techniques and quantify by High Performance Liquid Chromatography (HPLC) analysis. The structure of compound 19 was confirmed by single crystal XRD. From the overall preliminary in vitro data, analogs 14, 16, 19, 20, 24, 41, and 44 exhibited potential IC50 values in the nanomolar range between 4.7 ± 0.3 to 12.9 ± 1.1 nM against P. falciparum (Pf3D7) strains of human malaria parasite. Furthermore, these selective analogs were evaluated in vivo for their antimalarial potential against P. berghei and results revealed that analogue 24 rapidly kills the infected cell at asexual erythrocytic stage, with activity comparable to positive control chloroquine.

The "invisible" among the marginalised: Do gender and intersectionality matter in the Covid-19 response?

The spread of Covid-19 and the lockdown have brought in acute deprivation for rural, marginalised communities with loss of wages, returnee migrants and additional state-imposed barriers to accessing facilities and public provisions. Patriarchal norms amplified in such a crisis along with gender-blind state welfare policies have rendered women in these communities "invisible". This has impacted their access to healthcare, nutrition and social security, and significantly increased their unpaid work burden. Several manifestations of violence, and mental stress have surfaced, diminishing their bare minimum agency and rights and impacting their overall health and wellbeing. This article looks at these gendered implications in the context of rural, tribal and high migrant areas of South Rajasthan. We have adopted an intersectional approach to highlight how intersections of several structures across multiple sites of power: the public, the private space of the home and the woman's intimate space, have reduced them to ultra-vulnerable groups.

In vitro synergistic interaction of potent 4-aminoquinolines in combination with dihydroartemisinin against chloroquine-resistant Plasmodium falciparum.

High-grade chloroquine (CQ) resistance has been reported in malaria endemic geographical regions such as Papua New Guinea, northern Papua, and eastern and western provinces of Indonesia, along with low-level resistance in Vietnam, South Korea, Turkey, Burma, South America, and Madagascar. Studies on CQ drug resistance have revealed the association of P. falciparum chloroquine resistance transporter protein. Thus, we are in dire need of alternate chemotherapeutic agents which in combination with artemisinin (or its analogues) are efficacious against chloroquine-resistant strains. Such combinations may thwart the emergence of drug resistant strains, along with reducing the malaria burden. Hypothesizing that newer 4-aminoquinolines, earlier reported by our group, could be part of a combination therapy to efficiently treat malaria, we sought to evaluate these compounds, viz. 1m, 1o, 2c, and 2j against the erythrocytic stages of Plasmodium falciparum, strain 3D7 (chloroquine-sensitive) and strain Dd2 (chloroquine-resistant), in combination with dihydroartemisinin (DHA). Results revealed substantially synergistic interactions between the combination partners, which could be further established by their potential to inhibit hemozoin formation with increased efficiency when combined, as compared to the compounds assessed individually. Furthermore, aminoquinolines and DHA show distinct stage-specific profiles. Our results stand in strong support of the potential of these aminoquinoline derivatives to serve as partner drugs in antimalarial combinations to treat multiple-drug-resistant Plasmodium strains.

In vitro antiplasmodial efficacy of synthetic coumarin-triazole analogs.

Twenty two diverse coumarin-triazole derivatives were synthesized by alkylation of 7-hydroxy-4-methyl-coumarin followed by click chemistry at 7-position. These compounds were evaluated for their in vitro antiplasmodial activity against chloroquine sensitive strain of Plasmodium falciparum (3D7). Compound 9 (7-[1-(2, 4-dimethoxy-phenyl)-1H- [1-3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one) was found most active with IC50 value 0.763 ±â€¯0.0124 µg/mL. Further, the structure of compound 20 was characterized by single crystal X-ray diffraction. In view of impressive results, we considered it worthwhile to validate the results of in vitro antiplasmodial activity by assessing whether these compounds are capable of hampering the catalytic activity of DNA gyrase, thus preventing its supercoiling function.

Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities.

The present study was carried out in an attempt to synthesize a new class of antimicrobial and antiplasmodial agents by copper catalyzed click chemistry to afford 25 compounds 10-14(a-e) of 1,4-disubstituted-1,2,3-triazole derivatives of chalcones and flavones. The structures of the newly synthesized compounds were established by elemental analysis, IR, (1)H NMR, (13)C NMR and Mass spectral data. The newly synthesized compounds were evaluated for their antibacterial activity against Gram positive bacteria (Staphylococcus aureus, Enterococcus faecalis), Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Shigella boydii, Klebsiella pneumoniae) and antifungal activity against (Candida albicans, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Dermatophyte) as well as molds (Aspergillus niger, Aspergillus fumigatus). The antiplasmodial and cytotoxic activities of these compounds were also evaluated against human malaria parasite Plasmodium falciparum strain 3D7 and human hepato-cellular carcinoma cells (Huh-7), respectively. Compounds 10a, 10c, 10d, 12c and 14e showed promising antibacterial activity while compounds 10e, 11d, 11e, 12c, 13a, 13b, 13e, 14a and 14d showed good antifungal activity as compared to the corresponding standard drugs. Compound 10b was found to be the most active against Plasmodium falciparum while the remaining compounds showed moderate to weak antiplasmodial activity. However, cytotoxic activities of all compounds were found ineffective against Huh-7 cells.

4-Aminoquinoline derivatives: Synthesis, in vitro and in vivo antiplasmodial activity against chloroquine-resistant parasites.

Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in vivo. These 4-aminoquinolines cured BALB/c mice infected with P. berghei. The ED50 values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18 mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500 mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax.