The parasites that give rise to human African trypanosomiasis (HAT) are auxotrophs for various nutrients from the human host, including purines. They have specialist nucleoside transporters to import these metabolites. In addition to uptake of purine nucleobases and purine nucleosides, one of these transporters, the P2 transporter, can carry melamine derivatives; these derivatives are not substrates for the corresponding mammalian transporters. In this paper, we report the coupling of the melamine moiety to selected nitro heterocycles with the aim of selectively delivering these compounds to the parasites. Some compounds prepared have similar in vitro trypanocidal activities as melarsoprol, the principal drug used against late-stage HAT, with 50% growth inhibitory concentrations in the submicromolar range. Selected compounds were also evaluated in vivo in rodent models infected with Trypanosoma brucei brucei and T. brucei rhodesiense and showed pronounced activity and in two cases were curative without overt signs of toxicity. Compounds were also tested against other trypanosomatid pathogens, Leishmania donovani and Trypanosoma cruzi, and significant activity in vitro was noted for T. cruzi against which various nitro heterocycles are already registered for use.

Design and synthesis of a series of melamine-based nitroheterocycles with activity against Trypanosomatid parasites.

SUMMARY
Waterlogging the soil promotes epinastic growth of tomato petioles and increases the concentration of ethylene which can be extracted from various parts of the shoot. These concentrations exceed those normally required to promote epinasty when applied to the shoots of non-waterlogged plants.

Waterlogging also results in a rapid decline in the concentration of dissolved oxygen in the soil water. Low concentrations of oxygen around the roots of plants growing in nutrient solution promote epinastic growth and also increase ethylene concentration in the leaves. Experiments with detached shoots indicate that the root system is required for the response to low O2concentrations to develop.

Ethylene concentrations in the soil can increase during waterlogging to levels which may allow sufficient movement into the shoot to stimulate epinasty.

Treatment with substances which can inhibit the action of ethylene, such as carbon dioxide or 7-chloro-4-ethoxycarbonylmethoxy-5-methyl-2, 1,3-benzothiadiazole also inhibit the epinastic response in waterlogged plants, in plants with low O2 concentrations around the roots and in plants treated with ethylene. The internal level of carbon dioxide in the lower leaves is little affected by waterlogging for up to 96 h.

https://nph.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8137.1976.tb01434.x

Waterlogging and petiole epinasty in tomato: the role of ethylene and low oxygen

Publisher Summary This chapter discusses the development, chemistry, and mode of action of herbicide antidotes. Organic herbicides represent the most effective weapon available to farmers worldwide in their war against weeds. A fundamental reason for the widespread use of these chemicals in modern agriculture is their ability to control selectively a wide spectrum of weeds in a variety of crops. The concept of using herbicide antidotes offers a potential alternative for increasing the selectivity of available herbicides. A desirable herbicide antidote is a chemical agent that selectively protects crops from herbicide injury without protecting weeds. This selectivity is the result of either a very specific crop–herbicide–antidote interaction or a selective treatment such as the dressing of crop seeds with the antidote. Herbicide antidotes are developed primarily through random screening techniques that involve most combinations of important herbicides, major crops, and candidate antidotes. The timing of herbicide and antidote applications to the crop as well as differential intraspecific tolerance of crop cultivars to combinations of herbicides plus antidotes needs to be established for optimum effectiveness of herbicide antidotes in the field.

Herbicide Antidotes: Development, Chemistry, and Mode of Action

A number of well known polychlorinated chemicals are toxicologically and environmentally unsafe. Because of their persistence they are in the focus of public discussions against chlorine chemistry. However, chlorinated organic chemicals in the molecular weight range between 200 and 600 constitute an important and indispensable segment in the arsenal of existing biologically active chemicals used as pharmaceuticals or crop-protection agents. Over the course of time it has been found empirically that the introduction of a chlorine atom into one or more specific positions of a biologically active molecule may substantially improve the intrinsic biological activity. In some cases the presence of a chlorine atom is crucial for significant activity in compounds derived both from nature and chemical synthesis. But in other cases chlorination diminishes or abolishes biological activity, as shown for chlordane homologues. Thus a chlorine atom, like any other substituent, is a modulator of activity. Almost all non-reactive chlorinated chemicals and chlorine-free chemicals are devoid of any biological activity at the highest concentration typically used in primary screening tests for discovery of useful biological properties. The influence of a substituent such as chlorine on the biological activity of a potential drug or crop protection agent still has to be established empirically in biological experiments designed to detect desired activity or toxicological properties. Sometimes chlorine does prove to be the optimum for improvement of activity. Long-term rigorous investigations of several hundred chlorinated compounds, registered by the authorities as pharmaceutical drugs or crop-protection agents, show that the generalisation ‘all chlorinated chemicals are dangerous’, deduced from the negative toxicological properties of a hundred chlorinated and reactive compounds of low molecular weight that are relevant in terms of safe working conditions in the chemical industry and for ecological safety, is not justified. Chlorinated compounds are not necessarily toxic or dangerous. Highly reactive chemicals or polychlorinated compounds cannot be compared with regard to toxicological properties with unreactive compounds having a low degree of chlorination. The chlorine atom, as one of many possible substituents used in synthetic organic chemistry, will remain in the future one of the important tools for probing structure–activity relationships in life science research and as a molecular component in commercialised compounds, in order to provide safer, more selective and more environmentally compatible products with higher activity for medicine and agriculture.



© 1999 WILEY-VCH Verlag GmbH

Influence of chlorine substituents on biological activity of chemicals: a review.

A study of the dual electrophilic and pericyclic reactivity of 4,6-dinitrobenzofurazan (DNBZ, 2), 4,6-dinitro-2,1,3-benzothiadiazole (DNBS, 3), 4,6-dinitro-2,1,3-benzoselenadiazole (DNBSe, 4) is reported. Kinetic and thermodynamic measurements of the ease of covalent hydration of 2–4 to give the corresponding hydroxy σ-adducts C-2–C-4 have been carried out over a large pH range in aqueous solution. Analysis of the data has allowed a determination of the rate constants pertaining to the susceptibility of 2–4 to water attack as well as the pKa values for the σ-complexation processes. With pKa values ranging from 3.92 for DNBZ to 6.34 for DNBSe to 7.86 for DNBS, the electrophilic character of the three heteroaromatics is much closer to that of the superelectrophilic reference, i.e. 4,6-dinitrobenzofuroxan (DNBF, 1; pKa = 3.75), than that of the standard Meisenheimer electrophile 1,3,5-trinitrobenzene (TNB, pKa = 13.43). Most importantly, water is found to be an efficient nucleophile which contributes strongly to the formation of the adducts C-2 and C-4. This confirms a previous observation that a pKa value of ca. 8 is a primary requirement for having H2O competing effectively as a nucleophile with OH− in the formation of hydroxy σ-adducts. On the other hand, 2–4 are found to exhibit dienophilic and/or heterodienic behaviour on treatment with isoprene, 2,3-dimethylbutadiene, cyclopentadiene or cyclohexadiene, affording Diels–Alder mono- or di-adducts which have all been structurally characterized. A major finding is that the order of Diels–Alder reactivity follows clearly the order of electrophilicity, pointing to a direct relationship between superelectrophilic and pericyclic reactivity. This relationship is discussed.

Nitrobenzoxadiazoles and related heterocycles: a relationship between aromaticity, superelectrophilicity and pericyclic reactivity.

In view of their herbicidal properties a number of 2-(substituted amino) −4,6-dichloro-1,3,5-triazines was synthesized by a method described in the literature. The influence of the side chain on the herbicidal properties was determined. For this reason some derivatives mentioned in the literature were included to compare them with the new compounds in our biological tests.

Investigations on herbicides I. 2‐(Substituted amino)‐4,6‐dichloro‐1,3,5‐triazines

The synthesis and test results on the herbicidal and fungicidal activities of a large number of 2,1,3-benzothiadiazoles, mainly 4,5,7-trisubstituted derivatives, are described and discussed.

The chemistry, herbicidal and fungicidal activities of 2,1,3-benzothiadiazoles

Substituted alkoxycarbonylmethoxy-2,1,3-benzothiadiazoles

Synthesis and herbicidal activities of some new compounds generating 2,6-dichlorobenzonitrile

In a number of laboratory tests for herbicidal activity, 3-(4-cyclopropylphenyl)-l,1-dimethylurea, coded PH 4051. showed very promising results. This prompted us to investigate in detail the possible routes of synthesis of this compound, with the synthesis of 4-cyclopropylaniline as the main problem. In addition, the properties of this her­ bicide were tested both in the greenhouse and in the field. In this paper an account of this experimental work is pre­ sented.

3-(4-Cyclopropylphenyl)-1,1-dimethylurea, a selective herbicide for weed control in cereal grains

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