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The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

Background Cambodia is the epicentre of resistance emergence for virtually all antimalarial drugs. Selection and spread of parasites resistant to artemisinin-based combination therapy (ACT) is a major threat for malaria elimination, hence the need to renew the pool of effective treatments. Objectives To determine whether ACT resistance haplotypes could have an effect on ferroquine in vitro antimalarial activity. Methods In vitro susceptibility to ferroquine was measured for 80 isolates from Cambodia characterized for their molecular resistance profile to artemisinin, piperaquine and mefloquine. Results Among the 80 isolates tested, the overall median (IQR) IC50 of ferroquine was 10.9 nM (8.7–18.3). The ferroquine median (IQR) IC50 was 8.9 nM (8.1–11.8) for Pfk13 WT parasites and was 12.9 nM (9.5–20.0) for Pfk13 C580Y parasites with no amplification of Pfpm2 and Pfmdr1 genes. The median (IQR) IC50 of ferroquine for Pfk13 C580Y parasites with amplification of the Pfpm2 gene was 17.2 nM (14.5–20.5) versus 9.1 nM (7.9–10.7) for Pfk13 C580Y parasites with amplification of the Pfmdr1 gene. Conclusions Ferroquine exerts promising efficacy against ACT-resistant isolates. Whereas Pfpm2 amplification was associated with the highest parasite tolerance to ferroquine, the susceptibility range observed was in accordance with those measured in ACT resistance-free areas. This enables consideration of ferroquine as a relevant therapeutic option against ACT-resistant malaria.

Antimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could kill M. tuberculosis in diverse metabolic states. Here we report two chemically disparate classes of agents that kill M. tuberculosis both when it is replicating and when it is not. Under replicating conditions, the tricyclic 4-hydroxyquinolines and a barbituric acid analogue deplete intrabacterial magnesium as a mechanism of action, and for both compounds, mutations in CorA, a putative Mg2+/Co2+ transporter, conferred resistance to the compounds when M. tuberculosis was under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can kill M. tuberculosis in different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might cripple M. tuberculosis in a Mg2+-deficient intraphagosomal environment of macrophages., A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating Mycobacterium tuberculosis bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant M. tuberculosis. A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicating M. tuberculosis. Both families of compounds depleted M. tuberculosis of intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg2+/Co2+ ion channel, CorA. Excess extracellular Mg2+, but not other divalent cations, diminished the compounds’ cidality against replicating M. tuberculosis. These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show that M. tuberculosis magnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds.

This paper – which is based on the Thomas Franck Lecture held by the author at Humboldt University Berlin on 13 May 2019 – argues that the most likely development of international to be expected will be the coexistence of two “legal worlds”. On the one hand, an inter-State law brutally regulating political relations between human groups whitewashed by nationalism; on the other hand, a transnational or “a-national” law regulating economic relations between private as well as public interests. Further, the paper argues that there are two obvious victims – of very different nature – of this foreseeable evolution: the human being on the one hand, the certainty and effectiveness of the rule of law itself on the other hand., KFG Working Paper Series, 34

International relations have gone from a system regulated by the lawful resort to armed force to one theoretically prohibiting the use of force, but, without establishing a credible alternative. To lower the conditions under which the use of armed force remains lawful would open the door to every kind of abuse by resurrecting the old demons of “just war”, but to reject categorically such use also deprives the international society of effective means to prevent or end humanitarian disasters. This dilemma cannot be resolved through positive law which, as it stands, is certainly inclined to strictly maintain the principle of the prohibition of the use of force—interpreted reasonably.

Alain Pellet argues that we should not worry about fragmentation, given the multiplicity of international courts. To the contrary, he defends the dialogue among the many courts as contributing to the responsible development of international law. He responds to several criticisms concerning possible interpretative fragmentation; competing jurisdiction and forum shopping; as well as regional courts as a potential challenge to the global rule of law, holding that whilst fragmentation might be a problem in theory, it hardly ever occurs in practice. Pellet concludes that the several international courts are not a threat, but an enrichment of international jurisprudence.

In their eagerness to justify the “United States perspective” on the Kampala definition of the crime of aggression and on the International Criminal Court (ICC), Koh and Buchwald tend to invent imaginary enemies and to ascribe to them views that they do not actually hold. In so doing, the authors weaken a thesis that, in some respects, is not devoid of interest. From at least two points of view, however, their article is paradoxical, if not pathetic—exactly like the U.S. position.

Article 21 of the Rome Statute sets out a complex system of sources of applicable law. In addition to the Statute itself, which contains a relatively detailed list of crimes, Articles 21 includes the Elements of Crimes, a very detailed document which unnecessarily limits the scope of the crimes listed in the Statute and reveals mistrust with regard to the Court, the Rules of Procedure and Evidence, and the case law of the Court, despite the absence of stare decisis. In order to avoid risks of non liquet, Article 21 also refers to other norms and rules of international law. Article 21 establishes a hierarchy between the sources of law it refers to. It combines a formal hierarchy, on top of which lays the Statute, with a substantial hierarchy dominated by ‘internationally recognized human rights’ (Article 21(3)).

Nicaragua entered in the legend of the International Court of Justice in 1984 when it filed an Application against the United States, a ‘winning-bet’ which led to the epoch-making Judgment of 27 June 1986. It has since then based part of its ‘foreign legal policy’ on the World Court and entrusted it to settle most of its disputes with its neighbours. Before the Court, Nicaragua’s judicial strategy is marked by pragmatism and mutual confidence between Nicaragua, represented by the Agent, and Counsel which is stable even if it unavoidably evolves with the time. Globally Nicaragua’s judicial strategy appears as a success. Moreover, the fourteen cases Nicaragua participated in gave the Court an opportunity to deal with and clarify a significant number of questions of international law. Nicaragua deserves credit for that.

O caso Lotus, julgado pela Corte Permanente de Justica Internacional em 1927, e, ate a presente data, o precedente mais notavel quanto a delimitacao da soberania estatal no plano internacional. Apesar de a redacao do julgado parecer apontar de modo incontestavel para uma concepcao absoluta da soberania, sua adequada interpretacao e objeto de longos debates ao longo do ultimo seculo. Neste artigo, a decisao da CPJI e analisada a fundo, visando determinar se, de fato, esta pende a uma concepcao absoluta de soberania.

The purpose of this article is to revisit the long saga of the ILC Guide to Practice on Reservations to Treaties, as the Special Rapporteur has lived it for nearly 18 years and 16 reports. In its first part, the article recounts the elaboration procedure, pointing in particular to the elements of innovation and flexibility introduced in the process. The main one is the very type of instrument adopted, namely a Guide to Practice, and not a set of draft Articles that would eventually become a convention. In the second part, the main issues having retained the attention of the ILC, as well as of the other international bodies and of the academic community, are briefly recalled: the question of the unity or diversity of regimes, the permissibility of reservation and the status of the author of an impermissible reservation were among the most debated issues. Finally, the article explains the structure of the Guide to Practice.

International audience; [No abstract]

International audience; [No abstract]

International audience; [No abstract]

A high throughput phenotypic screening against Mycobacterium smegmatis led us to the discovery of a new class of bacteriostatic, highly hydrophobic antitubercular quinazolinones that potently inhibited the in vitro growth of either extracellular or intramacrophagic M. tuberculosis (Mtb), via modulation of an unidentified but yet novel target. Optimization of the initial hit compound culminated in the identification of potent but poorly soluble Mtb growth inhibitors, three of which were progressed to in vivo efficacy studies. Despite nanomolar in vitro potency and attractive PK properties, none of these compounds was convincingly potent in our in vivo mouse tuberculosis models. This lack of efficacy may be linked to the poor drug-likeness of the test molecules and/or to the properties of the target.

This presentation is twofold. The first part shows that the Nicaragua case played a significant role in reconciling the Third World with the International Court of Justice and, more generally, in revitalizing the Court. In the second part, the author, who was counsel for Nicaragua in that case, casts an eye as external analyst on the judgments of 1984, about which he has some reluctance, and 1986, which he largely approves of, even though Nicaragua did not win 100 per cent and some points may be debatable.

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.

In 2006 the International Law Commission adopted a set of Draft Articles on Diplomatic Protection that represent a departure from the traditional “Mavrommatis Fiction” which had patterned the institution ever since the Permanent Court of International Justice rendered its judgment in the Mavrommatis Palestine Concessions case. These “Notes” on the ILC's Draft Articles on Diplomatic Protection describe in detail how that “fiction” functioned and how the ILC's efforts have been instrumental in bringing about its slow, but sure, abandonment.

International audience; [No abstract]

PART I: THE ADVISORY PROCEEDINGS IN CONTEXT PART II: THE OPINION PART III: REACTIONS AND IMPLICATIONS PART IV: THE ROAD AHEAD BIBLIOGRAPHY INDEX

Veritable centre de gravite des Nations unies jusqu’au debut des annees quatre-vingt, l’Assemblee generale a progressivement sombre, avec la fin de la Guerre froide et la globalisation liberale, dans une logorrhee morose sans prise sur le reel. Elle n’est cependant pas depourvue d’atouts dans le cadre du « bicephalisme singulier » institue par les redacteurs de la Charte et elle a forge les instruments et les concepts lui permettant de pallier les carences du Conseil de securite. A cette fin, elle aurait pu avoir recours, lors des affaires du Kosovo et d’Iraq, a la « resolution Dean Acheson » de 1950, mais la volonte politique a manque.

There can be no doubt that the NATO action in Kosovo can (and must) be seen as legitimate, while, on the other hand, the jamming of the Security Council by China and Russia cannot. The actual lawfulness of the initiative, however, is more debatable, even though arguments based both on the UN Charter and on the law of state responsibility can be made in its favour and indeed become persuasive when seen together with, and in light of, Resolution 1244 (1999) of the Security Council. Nevertheless, it is essential that new 'community' mechanisms be found in the future in order to avoid being restricted to a choice between the 'Zorro' principle (as applied in Kosovo) and the Munich policy. A revival of Resolution 'Dean Acheson' (1950) and a deepening of the notion of 'state crime' and its consequences provide, among others, possibilities for limiting the need for legitimate but legally dubious unilateral uses of force. The task of a commentator may be both easy and difficult: easy since one may simply hand out good and bad marks and have the final word on the subject; difficult since, if the main authors have examined the issues thoroughly and intelligently, there may remain little to be said. It is definitely a case of the latter in taking up the task of commenting upon the articles by Ruth Wedgwood and Vera Gowlland-Debbas. Both authors have covered the issues in great depth and, what is more, I find myself largely in agreement with them. These authors have focused on a single debate seen at different angles — a debate that can be summarized in two short questions: — when is unilateral action lawful? and — when such an action is unlawful, can it be legitimate?

Despite the strong (probably growing) and passionate campaign against the notion of state crimes led by a handful of powerful states and relayed by some ILC members, including the new Special Rapporteur, the distinction between what is termed 'delicts' and what is termed 'crimes' answers an indisputable need and must be maintained. However, while the definition of crimes given in Article 19 of the ILC Draft Articles on State Responsibility is acceptable, though perhaps unduly sophisticated, the legal regime of these crimes as envisaged by the ILC is debatable. The method adopted to establish this regime has been grossly unsatisfactory and it must be accepted that the word 'crime' might be misleading. The concept is nevertheless indispensable in contemporary international law. As is well known, the International Law Commission decided in 1976 to include an article in its Draft Articles on State Responsibility which makes a distinction between 'normal' internationally wrongful acts, which it rather unfortunately called 'delicts', and exceptionally grave breaches of international law, which it termed, perhaps less unfortunately, 'international crimes'. 1 In this way, the ILC took up a suggestion made by its then Special Rapporteur, Roberto Ago, who, as early as 1939, had proposed such a distinction. 2 The ILC maintained this distinction when it completed the first reading of its Draft Articles in 1996, 3 despite strong (most likely growing) and passionate opposition, as several recent writings by members or former members of the Commission show. 4

Pellet Alain. Remarques sur une révolution inachevée, le projet d'articles de la Commission du Droit international sur la responsabilité des Etats. In: Annuaire français de droit international, volume 42, 1996. pp. 7-32.

During the debates on the draft articles, Sir Ian Brownlie harshly noted that the expression 'activity analogous to that of Governments' was 'a beautiful phrase that was completely useless, but was exactly what was needed'. This may well serve as a general comment on the whole draft: paradoxically, the main weaknesses of the Articles could also be seen as their strength. Undoubtedly, Sir Ian Brownlie put his finger on the core issue of the whole topic: when considering the responsibility of international organizations, could the International Law Commission (ILC) take the Articles on State responsibility, adopted in 2001 by the General Assembly, as the starting point for its reflection? The issue had already arisen in similar terms when the Commission had undertaken to study the topic of treaties concluded between States and international organizations or between two or more international organizations. Keywords: International Law Commission (ILC); Sir Ian Brownlie; State responsibility

The topic of this Lalive Lecture is austere. But it has the merit of opening wider perspectives than it seems at first glance. Through the prism that I have chosen, we can, I think, address interesting doctrinal issues which are not devoid of practical consequences: what is the nature of the ‘ICSID system’? A legal order? A ‘sub-system’ of general international law? A ‘sui generis’ Unidentified Juridical Object (UJO)—the refuge of doctrinal non possumus . . . ? And how, and to what extent, in this ‘system’ (a word to which I do not give any precise theoretical sense yet), does one use tools of general international law? Should we think in terms of relations between legal orders or legal systems? Or in terms of normative interactions? Although I do not pretend to give definitive answers to these broad questions, I will keep them in mind when trying to describe the areas in which ICSID tribunals resort to the jurisprudence of the World Court—a term which I take to include the International Court of Justice (ICJ) and its predecessor, the Permanent Court—and the way they do it. First, a preliminary question: why not ‘the ICSID jurisprudence in the decisions of the International Court of Justice’? The answer could simply be that it is not the topic of tonight’s conference. But there are also good reasons. First, there may be some doubt about the existence of ‘ICSID jurisprudence’; I do not get into the discussion of this vast issue, about which much has already been written. Let’s just say that I think

The Keynote Debate 'Anglo-American and Continental Traditions in Advocacy before International Courts and Tribunals' took place on 19 May 2013 in the Divinity School of St John's College, Cambridge, as part of the Second Annual CJICL Conference. The debate pitted Professor James Crawford against Professor Alain Pellet and was moderated by Professor Catherine Redgwell. It was made possible with the generous support of Freshfields Bruckhaus Deringer. The CJICL expresses its gratitude to Professors Crawford, Pellet and Redgwell for their kind permission to print this transcript; and to Naomi Burke, Godsglory Ifezue, Christopher Sargeant, Estelle Wolfers and Lawrence Li for their help with the transcription.

International audience; Bis-thiazolium salts are able to inhibit phosphatidylcholine biosynthesis in Plasmodium and to block parasite proliferation in the low nanomolar range. However, due to their physicochemical properties (i.e., permanent cationic charges, the flexibility, and lipophilic character of the alkyl chain), the oral bioavailability of these compounds is low. New series of bisthiazolium-based drugs have been designed to overcome this drawback. They feature linker rigidification via the introduction of aromatic rings and/or a decrease in the overall lipophilicity through the introduction of heteroatoms. On the basis of the structure−activity relationships, a few of the promising compounds (9, 10, and 11) were found to exhibit potent antimalarial in vitro and in vivo activities (EC50 < 10 nM and ED50 ip < 0.7 mg/kg).

1. La place faite au droit international dans la Charte des Nations Unies est des plus rgduites. Alors que les combats font encore rage dans le Pacifique, 16gitimement, l'obsession du maintien de la paix et de la securite internationales domine a Dumberton Oaks a San Francisco. Tout au plus concede-t'on que le «respect des obligations nees des traites et autres sources du droit» devrait en etre une cons6quence (preambule, alinea 3) et que «l'ajustement ou le reglement de differends ou de situation, de caractere international, susceptibles de mener a une rupture de la paix» doit etre realise «par des moyens pacifiques, conformement aux principes de la justice toujours citee en premier lieu et du droit international (article l, paragraphe 1)». La pietre estime dans laquelle est tenue le droit international comme moyen d'assumer le maintien de la paix et de la securite* internationales apparait, de maniere presque caricaturale, dans le paragraphe 2 de 1'article 94 qui reconnait au Conseil de s6curit6 une comp6tencc discrdtionnaire pour apprdcier les suites qu'il convient de donner ou non a un refus d'execution d'un arret de la Cour intemationale de justice.

International audience; We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.

International audience; Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches.

This chapter contains notes on the jurisprudence of the International Court of Justice in the field of international responsibility. The law of international responsibility of the State has always been an essential guard. The arbitral tribunals of the nineteenth and early twentieth centuries laid the foundations, especially in distressed areas between European states and the United States of America to Latin American countries to meet their international obligations in respect to especially foreign interests threatened by repeated revolutions and instability then in the sub-continent. The ILC Articles on Responsibility of the state generally reflect on customary rules. By applying these rules, the Court has given interesting clarification of their interpretation and scope regarding the system of international responsibility and notion of an internationally wrongful act , the attribution to the state of unlawful conduct and the content and implementation of the responsibility . Keywords:Cour internationale de Justice; ILC article; International Court of Justice; international responsibility; internationally wrongful act; responsabilite internationale; state of unlawful conduct