What happens after colonial industries have run their course—after the factory closes and the fields go fallow? Set in the cinchona plantations of India’s Darjeeling Hills, Quinine’s Remains ...chronicles the history and aftermaths of quinine. Harvested from cinchona bark, quinine was malaria’s only remedy until the twentieth-century advent of synthetic drugs, and it was vital to the British Empire. Today, the cinchona plantations—and the roughly fifty thousand people who call them home—remain. Their futures, however, are unclear. The Indian government has threatened to privatize or shut down this seemingly obsolete and crumbling industry, but the plantation community, led by strident trade unions, has successfully resisted. Overgrown cinchona fields and shuttered quinine factories may appear the stuff of postcolonial and postindustrial ruination, but quinine’s remains are not dead. Rather, they have become the site of urgent efforts to redefine land and life for the twenty-first century. Quinine’s Remains offers a vivid historical and ethnographic portrait of what it means to forge life after empire. “Written in a deeply engaging and accessible style, this pathbreaking book explores the world of plantation laborers, whose voices are either hidden or silenced in scholarly literature on economic botany.” — ROHAN DEB ROY, author of Malarial Subjects “Accounts of science and empire describe the centrality of cinchona to the colonial project in India, but we know little about what came after. Quinine’s Remains is an ethnographically rich and thoroughly readable story of what it means to live in the wake of medical innovation on contemporary cinchona plantations.” — SARAH BESKY, author of Tasting Qualities
The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery ...of two diverse lead series imidazo1,2-apyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure–activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.
Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with ...complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its current usage and provides insight into its appropriate future use in the treatment of malaria. In light of recent research findings intravenous artesunate should be the first-line drug for severe malaria, with quinine as an alternative. The role of rectal quinine as pre-referral treatment for severe malaria has not been fully explored, but it remains a promising intervention. In pregnancy, quinine continues to play a critical role in the management of malaria, especially in the first trimester, and it will remain a mainstay of treatment until safer alternatives become available. For uncomplicated malaria, artemisinin-based combination therapy (ACT) offers a better option than quinine though the difficulty of maintaining a steady supply of ACT in resource-limited settings renders the rapid withdrawal of quinine for uncomplicated malaria cases risky. The best approach would be to identify solutions to ACT stock-outs, maintain quinine in case of ACT stock-outs, and evaluate strategies for improving quinine treatment outcomes by combining it with antibiotics. In HIV and TB infected populations, concerns about potential interactions between quinine and antiretroviral and anti-tuberculosis drugs exist, and these will need further research and pharmacovigilance.
We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C−H activation and an aldol reaction, to unite the two heterocyclic ...moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (−)‐quinine, the first synthesis of unnatural (+)‐quinine, and also provides access to unprecedented C3‐aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (−)‐quinine both in vitro and in mice infected with Plasmodium berghei.
Revisiting an old friend: A novel approach to the classical natural product quinine is based on two stereoselective key steps, namely a C(sp3)−H activation and an aldol reaction. This strategy enables the preparation of both antipodes of the target as well as novel synthetic analogues that display enhanced in vivo antimalarial activity.
The importance of natural products in the treatment of human disease is well documented. While natural products continue to have a profound impact on human health, chemists have succeeded in ...generating semisynthetic analogues that sometimes overshadow the original natural product in terms of clinical significance. Synthetic efforts based on natural products have primarily focused on improving their drug-like features while targeting utility in the same biological space. A less documented phenomenon is that natural products can serve as powerful starting materials to generate drug substances with novel therapeutic utility that is unrelated to the biological space of the natural product starting material. In this Perspective, examples of natural product derived marketed drugs with therapeutic utility in clinical space that is different from the biological profile of the starting material are presented, demonstrating that this is not merely a theoretical concept but both a clinical reality and an underexplored opportunity.
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SNM1A is a zinc-dependent nuclease involved in the removal of interstrand crosslink lesions from DNA. Inhibition of interstrand crosslink repair enzymes such as SNM1A is a promising ...strategy for improving the efficacy of crosslinking chemotherapy drugs. Initial studies have demonstrated the feasibility of developing SNM1A inhibitors, but the full potential of this enzyme as a drug target has yet to be explored. Herein, the synthesis of a family of squaramide- and thiosquaramide-bearing nucleoside derivatives and their evaluation as SNM1A inhibitors is reported. A gel electrophoresis assay was used to identify nucleoside derivatives bearing an N-hydroxysquaramide or squaric acid moiety at the 3′-position, and a thymidine derivative bearing a 5′-thiosquaramide, as candidate SNM1A inhibitors. Quantitative IC50 determination showed that a thymidine derivative bearing a 5′-thiosquaramide was the most potent inhibitor, followed by a thymidine derivative bearing a 3′-squaric acid. UV–Vis titrations were carried out to evaluate the binding of the (thio)squaramides to zinc ions, allowing the order of inhibitory potency to be rationalised. The membrane permeability of the active inhibitors was investigated, with several compounds showing promise for future in vivo applications.
The asymmetric catalytic 1,6-addition of p-QMs with racemic oxindoles under the bifunctional catalysis of C2-symmetric dimeric Cinchona-derived squaramide is described. This tertiary amine-squaramide ...catalyzed reaction provides a diastereoselective and enantioselective approach to the effective assembly of diverse diarylmethine-substituted oxindoles having vicinal tertiary and quaternary stereocenters.
Synthetic ion transporters have attracted tremendous attention for their therapeutic potential against various ion-transport-related diseases, including cancer. Inspired by the structure and ...biological activities of natural products, we synthesized a small series of squaramide and thiourea derivatives of quinine and investigated their ion transport activities. The involvement of a quinuclidine moiety for the cooperative interactions of Cl
and H
ions with the thiourea or squaramide moiety resulted in an effectual transport of these ions across membranes. The interference of ionic equilibrium by the potent Cl
ion carrier selectively induced cancer cell death by endorsing caspase-arbitrated apoptosis. In vivo assessment of the potent ionophore showed an efficient reduction in tumor growth with negligible immunotoxicity to other organs.
We report a general method for the synthesis of chiral thiosquaramides, a class of bifunctional catalysts not previously described in the literature. Thiosquaramides are found to be more acidic and ...significantly more soluble in nonpolar solvents than their oxosquaramide counterparts, and they are excellent catalysts for the unreported, enantioselective conjugate addition reaction of the barbituric acid pharmacaphore to nitroalkenes, delivering the chiral barbiturate derivatives in high yields and high enantioselectivities, even with catalyst loadings as low as 0.05 mol%.
Malaria is a tropical disease, prevalent in Southeast Asia and Africa, resulting in over half a million deaths annually; efforts to develop new antimalarial agents are therefore particularly ...important. Quinine continues to play a role in the fight against malaria, but quinoline derivatives are more widely used. Drugs based on the quinoline scaffold include chloroquine and primaquine, which are able to act against the blood and liver stages of the parasite's life cycle. The purpose of this review is to discuss reported biologically active compounds based on either the quinine or quinoline scaffold that may have enhanced antimalarial activity. The review emphasises hybrid molecules, and covers advances made in the last five years. The review is divided into three sections: modifications to the quinine scaffold, modifications to aminoquinolines and finally metal-containing antimalarial compounds.
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•Malaria continues to affect over 200 millions people worldwide.•Quinine and aminoquinolines remain important drugs in the fight against malaria.•Novel antimalarials are needed due to resistance towards current treatments.•Modifications to chloroquine allow rapid access to potential antimalarial agents.
![Discovery of Imidazo[1,2‑a]...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0022-2623/small "Discovery of Imidazo[1,2‑a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis")
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