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1.
ACS Infect Dis ; 9(2): 221-238, 2023 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-36606559

RESUMEN

Mycobacterium tuberculosis cytochrome bd quinol oxidase (cyt bd), the alternative terminal oxidase of the respiratory chain, has been identified as playing a key role during chronic infection and presents a putative target for the development of novel antitubercular agents. Here, we report confirmation of successful heterologous expression of M. tuberculosis cytochrome bd. The heterologous M. tuberculosis cytochrome bd expression system was used to identify a chemical series of inhibitors based on the 2-aryl-quinolone pharmacophore. Cytochrome bd inhibitors displayed modest efficacy in M. tuberculosis growth suppression assays together with a bacteriostatic phenotype in time-kill curve assays. Significantly, however, inhibitor combinations containing our front-runner cyt bd inhibitor CK-2-63 with either cyt bcc-aa3 inhibitors (e.g., Q203) and/or adenosine triphosphate (ATP) synthase inhibitors (e.g., bedaquiline) displayed enhanced efficacy with respect to the reduction of mycobacterium oxygen consumption, growth suppression, and in vitro sterilization kinetics. In vivo combinations of Q203 and CK-2-63 resulted in a modest lowering of lung burden compared to treatment with Q203 alone. The reduced efficacy in the in vivo experiments compared to in vitro experiments was shown to be a result of high plasma protein binding and a low unbound drug exposure at the target site. While further development is required to improve the tractability of cyt bd inhibitors for clinical evaluation, these data support the approach of using small-molecule inhibitors to target multiple components of the branched respiratory chain of M. tuberculosis as a combination strategy to improve therapeutic and pharmacokinetic/pharmacodynamic (PK/PD) indices related to efficacy.


Asunto(s)
Antituberculosos , Mycobacterium tuberculosis , Quinolonas , Antituberculosos/farmacología , Citocromos/antagonistas & inhibidores , Complejo IV de Transporte de Electrones/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Quinolonas/farmacología
2.
J Comp Psychol ; 136(4): 255-269, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36342448

RESUMEN

Associating with kin provides individual benefits but requires that these relationships be detectable. In humans, facial phenotype matching might help assess paternity; however, evidence for it is mixed. In chimpanzees, concealing visual cues of paternity may be beneficial due to their promiscuous mating system and the considerable risk of infanticide by males. On the other hand, detecting kin can also aid chimpanzees in avoiding inbreeding and in forming alliances that improve kin-mediated fitness. Although previous studies assessing relatedness based on facial resemblance in chimpanzees exist, they used images of captive populations in whom selection pressures and reproductive opportunities are controlled and only assessed maternity or paternity of adult offspring. In natural populations, the chances of infanticide are highest during early infancy, suggesting that young infants would benefit most from paternity concealment, whereas adults and subadults would benefit from the detection of all types of kin, including half-siblings. In our experiment, we conducted an online study with human participants, in which they had to assess the relatedness of chimpanzees based on facial similarity. To address previous methodological constraints, we used chimpanzee images across all ages, as well as maternal and paternal half-siblings. We found that kin status was detected above chance across all relatedness categories, with easier kin detection of father-offspring pairs, females, and older chimpanzees. Together, these findings support the existence of paternity confusion in infant chimpanzees and provide a possible mechanism for incest avoidance and kin-based social alliances in older individuals. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Asunto(s)
Pan troglodytes , Reconocimiento en Psicología , Embarazo , Masculino , Adulto , Humanos , Femenino , Animales , Anciano , Cara , Señales (Psicología) , Hermanos
3.
Behav Processes ; : 104627, 2022 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-35364224

RESUMEN

Dominance hierarchies vary between species and possess particular characteristics depending on the distribution and abundance of food resources that affect the competitive regime. Bonobos have been described as having female intersexual dominance, based mainly on female coalitionary support against males, and more egalitarian hierarchies than chimpanzees. In this study, we tested whether female intersexual dominance is dependent on female coalitions or whether it still arises when only dyadic interactions are considered. We also examined the role of food abundance in shaping dominance style in a wild population of bonobos in Wamba, Democratic Republic of Congo. We found partial support concerning our first prediction in which we expected a male dominance over females when only dyadic agonistic interactions were considered because females were not systematically dominant over males, finding instead an intersexual codominance pattern. We failed to find support for our second prediction that hierarchies become more despotic under low fruit abundance, in fact, we found the opposite pattern. We discuss that codominance based on dyadic interactions in this group may arise as a consequence of male deference rather than females winning conflicts against males and that more despotic hierarchies during high fruit season may arise as a consequence of competition for high-quality resources or variation in party size.

4.
Primates ; 61(1): 69-82, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31134473

RESUMEN

Infanticide is well documented in chimpanzees and various hypotheses have been proposed to explain this behavior. However, since infanticide by chimpanzees is relatively rare, it has thus far not been possible to thoroughly test these hypotheses. Here we present an analysis of the largest dataset of infanticides from a single community of chimpanzees, a full record of all intra-community infanticides and failed attempts at infanticide over a 24-year period for the Sonso community of chimpanzees in the Budongo Forest, Uganda. We use these data to test four hypotheses for this behavior: the sexual selection hypothesis, male mating competition, resource competition, and meat acquisition. Our dataset consisted of 33 attacks on 30 victims, 11 of which were 'definite' infanticides, four of which 'almost certain', and nine were 'suspected', while nine were 'attempted' infanticides. The majority of attacks where the perpetrators were known (23) had only male attackers and victims were disproportionately young (two-thirds of victims with known ages were under 1 week old). Our data best support the sexual selection hypothesis for infanticide. Cannibalism was infrequent and partial, suggesting meat acquisition was a by-product of infanticide, and there was no evidence to suggest that infanticide was part of a male strategy to eliminate future competitors. Infanticide by females was rare, but we suggest sexual selection, operating through intra-sexual competition, may also be responsible for infanticide by females.


Asunto(s)
Canibalismo , Pan troglodytes/psicología , Animales , Conducta Animal , Femenino , Masculino , Uganda
5.
Am J Phys Anthropol ; 168(1): 3-9, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30302748

RESUMEN

OBJECTIVES: Infanticide by males is common in mammals. According to the sexual selection hypothesis, the risk is inversely related to infant age because the older the infant, the less infanticide can shorten lactational amenorrhea; risk is also predicted to increase when an infanticidal male's chance of siring the replacement infant is high. Infanticide occurs in chimpanzees (Pan troglodytes), a species in which male dominance rank predicts paternity skew. Infanticidal male chimpanzees (if low-ranking) are unlikely to kill their own offspring, whereas those who are currently rising in rank, particularly when this rise is dramatic, have an increased likelihood of fathering potential future infants relative to any existing ones. Given that mothers should behave in ways that reduce infanticide risk, we predicted that female chimpanzees, and specifically those with younger, more vulnerable infants, would attempt to adjust the exposure of their infants to potentially infanticidal males. Specifically, mothers of young infants should reduce their association with adult males in general, and to a greater extent, with both low-ranking males and those rising in rank from a position where paternity of current infants was unlikely, to a rank where the probability of siring the next infant is significantly higher. We also investigated the alternative possibility that rather than avoiding all adult males, mothers would increase association with males of stable high rank on the basis that such males could offer protection against infanticide. MATERIALS AND METHODS: We examined data on female association patterns collected from the Budongo Forest, Uganda, during a period encompassing both relative stability in the male hierarchy and a period of instability with a mid-ranking male rising rapidly in rank. RESULTS: Using linear mixed models, we found that mothers reduced their association with the rank-rising male, contingent on infant age, during the period of instability. We also found evidence that females preferentially associated with a potential protector male during the high-risk period. DISCUSSION: Our results support the sexually selected hypothesis for infanticide and demonstrate that female chimpanzees are sensitive to the relative risks posed by adult males.


Asunto(s)
Agresión/fisiología , Conducta Animal/fisiología , Pan troglodytes/fisiología , Animales , Animales Recién Nacidos , Femenino , Jerarquia Social , Masculino , Madres
6.
Int J Primatol ; 38(3): 427-447, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28680188

RESUMEN

Among studies of social species, it is common practice to rank individuals using dyadic social dominance relationships. The Elo-rating method for achieving this is powerful and increasingly popular, particularly among studies of nonhuman primates, but suffers from two deficiencies that hamper its usefulness: an initial burn-in period during which the model is unreliable and an assumption that all win-loss interactions are equivalent in their influence on rank trajectories. Here, I present R code that addresses these deficiencies by incorporating two modifications to a previously published function, testing this with data from a 9-mo observational study of social interactions among wild male chimpanzees (Pan troglodytes) in Uganda. I found that, unmodified, the R function failed to resolve a hierarchy, with the burn-in period spanning much of the study. Using the modified function, I incorporated both prior knowledge of dominance ranks and varying intensities of aggression. This effectively eliminated the burn-in period, generating rank trajectories that were consistent with the direction of pant-grunt vocalizations (an unambiguous demonstration of subordinacy) and field observations, as well as showing a clear relationship between rank and mating success. This function is likely to be particularly useful in studies that are short relative to the frequency of aggressive interactions, for longer-term data sets disrupted by periods of lower quality or missing data, and for projects investigating the relative importance of differing behaviors in driving changes in social dominance. This study highlights the need for caution when using Elo-ratings to model social dominance in nonhuman primates and other species.

7.
J Med Chem ; 60(9): 3703-3726, 2017 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-28304162

RESUMEN

A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ∼100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further ∼90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.


Asunto(s)
Mycobacterium tuberculosis/efectos de los fármacos , Quinolonas/síntesis química , Quinolonas/farmacología , Animales , Células CACO-2 , Espectroscopía de Resonancia Magnética con Carbono-13 , Diseño de Fármacos , Transporte de Electrón/efectos de los fármacos , Células Hep G2 , Ensayos Analíticos de Alto Rendimiento , Humanos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Quinolonas/química , Quinolonas/farmacocinética , Ratas , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Pruebas de Toxicidad
8.
Sci Rep ; 6: 20634, 2016 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-26856371

RESUMEN

The evolution of cooperation remains a central issue in socio-biology with the fundamental problem of how individuals minimize the risks of being short-changed ('cheated') should their behavioural investment in another not be returned. Economic decisions that individuals make during interactions may depend upon the presence of potential partners nearby, which offers co operators a temptation to defect from the current partner. The parcelling model posits that donors subdivide services into parcels to force cooperation, and that this is contingent on opportunities for defection; that is, the presence of bystanders. Here we test this model and the effect of bystander presence using grooming interactions of wild chimpanzees. We found that with more bystanders, initiators gave less grooming at the beginning of the bout and were more likely to abandon a grooming bout, while bouts were less likely to be reciprocated. We also found that the groomer's initial investment was not higher among frequent groomers or stronger reciprocators, suggesting that contrary to current assumptions, grooming decisions are not based on trust, or bonds, within dyads. Our work highlights the importance of considering immediate social context and the influence of bystanders for understanding the evolution of the behavioural strategies that produce cooperation.


Asunto(s)
Evolución Biológica , Aseo Animal/fisiología , Pan troglodytes , Conducta Social , Confianza/psicología , Animales , Masculino , Pan troglodytes/fisiología , Pan troglodytes/psicología
9.
Behav Ecol Sociobiol ; 69(6): 1039-1052, 2015 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-26279605

RESUMEN

Across taxa, males employ a variety of mating strategies, including sexual coercion and the provision, or trading, of resources. Biological market theory (BMT) predicts that trading of commodities for mating opportunities should exist only when males cannot monopolize access to females and/or obtain mating by force, in situations where power differentials between males are low; both coercion and trading have been reported for chimpanzees (Pan troglodytes). Here, we investigate whether the choice of strategy depends on the variation in male power differentials, using data from two wild communities of East African chimpanzees (Pan troglodytes schweinfurthii): the structurally despotic Sonso community (Budongo, Uganda) and the structurally egalitarian M-group (Mahale, Tanzania). We found evidence of sexual coercion by male Sonso chimpanzees, and of trading-of grooming for mating-by M-group males; females traded sex for neither meat nor protection from male aggression. Our results suggest that the despotism-egalitarian axis influences strategy choice: male chimpanzees appear to pursue sexual coercion when power differentials are large and trading when power differentials are small and coercion consequently ineffective. Our findings demonstrate that trading and coercive strategies are not restricted to particular chimpanzee subspecies; instead, their occurrence is consistent with BMT predictions. Our study raises interesting, and as yet unanswered, questions regarding female chimpanzees' willingness to trade sex for grooming, if doing so represents a compromise to their fundamentally promiscuous mating strategy. It highlights the importance of within-species cross-group comparisons and the need for further study of the relationship between mating strategy and dominance steepness.

10.
Anim Behav ; 99: 1-154, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25580017

RESUMEN

Biological market theory models the action of natural selection as a marketplace in which animals are viewed as traders with commodities to offer and exchange. Studies of female Old World monkeys have suggested that grooming might be employed as a commodity to be reciprocated or traded for alternative services, yet previous tests of this grooming-trade model in wild adult male chimpanzees have yielded mixed results. Here we provide the strongest test of the model to date for male chimpanzees: we use data drawn from two social groups (communities) of chimpanzees from different populations and give explicit consideration to variation in dominance hierarchy steepness, as such variation results in differing conditions for biological markets. First, analysis of data from published accounts of other chimpanzee communities, together with our own data, showed that hierarchy steepness varied considerably within and across communities and that the number of adult males in a community aged 20-30 years predicted hierarchy steepness. The two communities in which we tested predictions of the grooming-trade model lay at opposite extremes of this distribution. Second, in accord with the grooming-trade model, we found evidence that male chimpanzees trade grooming for agonistic support where hierarchies are steep (despotic) and consequent effective support is a rank-related commodity, but not where hierarchies are shallow (egalitarian). However, we also found that grooming was reciprocated regardless of hierarchy steepness. Our findings also hint at the possibility of agonistic competition, or at least exclusion, in relation to grooming opportunities compromising the free market envisioned by biological market theory. Our results build on previous findings across chimpanzee communities to emphasize the importance of reciprocal grooming exchanges among adult male chimpanzees, which can be understood in a biological markets framework if grooming by or with particular individuals is a valuable commodity.

11.
Biol Rev Camb Philos Soc ; 89(2): 356-74, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24393574

RESUMEN

Mating strategies are sets of decisions aimed at maximizing reproductive success. For male animals, the fundamental problem that these strategies address is attaining mating access to females in a manner that maximizes their chances of achieving paternity. For chimpanzees (Pan troglodytes), despite substantial interest in mating strategies, very little attention has been paid to the most fundamental problem that mating strategies need to solve: finding mates. Only a single model, Dunbar's general model of male mating strategies, exists to explain mate-searching behaviour in chimpanzees. Under this model, males in most populations are regarded as pursuing a 'roving' strategy: searching for and sequestering fertile females who are essentially passive with respect to mate searching. The roving mating strategy is an assumption deeply embedded in the way chimpanzee behaviour is considered; it is implicit in the conventional model for chimpanzee social structure, which posits that male ranging functions both to monitor female reproductive state and to ward these females from other groups of males through collective territoriality: essentially, ranging as mating effort. This perspective is, however, increasingly at odds with observations of chimpanzee behaviour. Herein, I review the logic and evidence for the roving-male mating strategy and propose a novel alternative, a theoretical framework in which roving is a strategy pursued by female chimpanzees in order to engage successfully in promiscuous mating. Males, unable to thwart this female strategy, instead maximise the number of reproductive opportunities encountered by focusing their behaviour on countering threats to health, fertility and reproductive career. Their prolonged grooming bouts are seen, in consequence, as functioning to mitigate the negative impacts of socially induced physiological stress. In this new framework, the roving-male strategy becomes, at best, a 'best of a bad job' alternative for low-ranking males when faced with high levels of competition for mating access. Male chimpanzees do not search for mates, but for one another, for food, and, at times, for rivals in other communities. To the extent that female promiscuity functions to counter infanticide risk, mate searching by female chimpanzees-and any associated costs-can be seen as an unavoidable consequence of male sexual coercion. This novel framework is a better fit to the available data than is the conventional account. This review highlights the desperate need for additional work in an area of chimpanzee biology that has been somewhat neglected, perhaps in part because assumptions of roving males have remained unquestioned for too long. It also highlights the need, across taxa, to revisit and revise theory, and to test old assumptions, when faced with contrary data.


Asunto(s)
Pan troglodytes/fisiología , Conducta Sexual Animal/fisiología , Animales , Femenino , Masculino , Conducta Social
12.
Am J Primatol ; 75(8): 789-97, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23436438

RESUMEN

Chimpanzees (Pan troglodytes) are capable of extreme violence. They engage in inter-group, sometimes lethal, aggression that provides the winners with an opportunity to enlarge their territory, increase their food supply and, potentially, attract more mates. Lethal violence between adult males also occurs within groups but this is rare; to date, only four cases (three observed and one inferred) have been recorded despite decades of observation. In consequence, the reasons for within-group lethal violence in chimpanzees remain unclear. Such aggression may be rare due to the importance of coalitions between males during inter-group encounters; cooperation between males is also thought to be key in the defense or advancement of social rank within the group. Previous accounts of within-group lethal violence concern victims who were low-ranking males; here we provide the first account of the killing of an incumbent alpha male by a coalition of adult males from the same community. We found no clear evidence that the alpha male's position was under threat during the months before the lethal attack: the male dominance hierarchy was highly stable, with low rates of male-male aggression, and there were no significant changes in social interactions (i.e. grooming and aggression) between the alpha male and the other adult males. Two of the four attackers were former alpha males and were the individuals with whom the victim appeared, in the period preceding his death, to be most strongly affiliated: his most frequent grooming partners and those with whom he spent most time in proximity. The lethal attack triggered a period of instability in the male hierarchy and was likely an opportunistic attempt to seize alpha status by the third-ranking male.


Asunto(s)
Pan troglodytes/fisiología , Predominio Social , Violencia , Envejecimiento , Animales , Masculino , Tanzanía
13.
J Antimicrob Chemother ; 68(4): 869-80, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23228936

RESUMEN

OBJECTIVES: Phenothiazines have been shown to exhibit in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb) and multidrug-resistant Mtb. They are predicted to target the genetically validated respiratory chain component type II NADH:quinone oxidoreductase (Ndh). Using a set of compounds containing the phenothiazine pharmacophore, we have (i) investigated whether chemical validation data support the molecular target and (ii) evaluated pharmacophore tractability for further drug development. METHODS: Recombinant Mtb Ndh was generated and its functionality confirmed by steady-state kinetics. Pharmacodynamic profiling of the phenothiazines, including antitubercular efficacy in aerobic and O2-limited conditions, time-kill assays and isobole analyses against first-line antituberculars, was performed. Potential mitochondrial toxicity was assessed in a modified HepG2 cell-line assay and against bovine cytochrome bc1. RESULTS: Steady-state kinetic analyses revealed a substrate preference for coenzyme Q2 and an inability to utilize NADPH. A positive correlation between recombinant Ndh inhibition and kill of aerobically cultured Mtb was observed, whilst enhanced potency was demonstrated in a hypoxic model. Time-kill studies revealed the phenothiazines to be bactericidal whilst isobolograms exposed antagonism with isoniazid, indicative of intracellular NADH/NAD(+) couple perturbation. At therapeutic levels, phenothiazine-mediated toxicity was appreciable; however, specific mitochondrial targeting was excluded. CONCLUSIONS: Data generated support the hypothesis that Ndh is the molecular target of phenothiazines. The favourable pharmacodynamic properties of the phenothiazines are consistent with a target product profile that includes activity against dormant/persistent bacilli, rapid bactericidal activity and activity against drug-resistant Mtb by a previously unexploited mode of action. These properties warrant further medicinal chemistry to improve potency and safety.


Asunto(s)
Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Fenotiazinas/farmacología , Antituberculosos/química , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Viabilidad Microbiana/efectos de los fármacos , Mycobacterium tuberculosis/fisiología , Fenotiazinas/química
14.
PLoS One ; 7(4): e34669, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22493709

RESUMEN

Red is a colour that induces physiological and psychological effects in humans, affecting competitive and sporting success, signalling and enhancing male social dominance. The colour is also associated with increased sexual attractiveness, such that women associated with red objects or contexts are regarded as more desirable. It has been proposed that human males have a biological predisposition towards the colour red such that it is 'sexually salient'. This hypothesis argues that women use the colour red to announce impending ovulation and sexual proceptivity, with this functioning as a proxy signal for genital colour, and that men show increased attraction in consequence. In the first test of this hypothesis, we show that contrary to the hypothesis, heterosexual men did not prefer redder female genitalia and, by extension, that red is not a proxy signal for genital colour. We found a relative preference for pinker genital images with redder genitalia rated significantly less sexually attractive. This effect was independent of raters' prior sexual experience and variation in female genital morphology. Our results refute the hypothesis that men's attraction to red is linked to an implied relationship to genital colour and women's signalling of fertility and sexual proceptivity.


Asunto(s)
Conducta de Elección/fisiología , Genitales Femeninos/fisiología , Conducta Sexual/psicología , Adolescente , Adulto , Color , Femenino , Humanos , Masculino , Motivación
15.
J Med Chem ; 55(7): 3144-54, 2012 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-22380711

RESUMEN

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 µM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria.


Asunto(s)
Antimaláricos/química , Bases de Datos Factuales , Plasmodium falciparum/enzimología , Proteínas Protozoarias/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Quinona Reductasas/antagonistas & inhibidores , Antimaláricos/farmacología , Teorema de Bayes , Ensayos Analíticos de Alto Rendimiento , Informática , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Análisis de Componente Principal , Proteínas Protozoarias/química , Quinona Reductasas/química
16.
J Med Chem ; 55(5): 1831-43, 2012 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-22364416

RESUMEN

A program was undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone (HDQ), and this was used along with a range of chemoinformatics methods in the rational selection of 17 000 compounds for high-throughput screening. Twelve distinct chemotypes were identified and briefly examined leading to the selection of the quinolone core as the key target for structure-activity relationship (SAR) development. Extensive structural exploration led to the selection of 2-bisaryl 3-methyl quinolones as a series for further biological evaluation. The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other respiratory enzymes (inhibitory IC(50) against PfNDH2 of 16 nM), and demonstrates low cytotoxicity and high metabolic stability in the presence of human liver microsomes. This lead compound and its phosphate pro-drug have potent in vivo antimalarial activity after oral administration, consistent with the target product profile of a drug for the treatment of uncomplicated malaria. Other quinolones presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc(1), and studies to determine the potential advantage of this dual-targeting effect are in progress.


Asunto(s)
Antimaláricos/síntesis química , Plasmodium falciparum/enzimología , Quinolonas/síntesis química , Quinona Reductasas/antagonistas & inhibidores , Administración Oral , Animales , Antimaláricos/química , Antimaláricos/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Complejo III de Transporte de Electrones/antagonistas & inhibidores , Humanos , Técnicas In Vitro , Malaria/tratamiento farmacológico , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Quinolonas/química , Quinolonas/farmacología , Relación Estructura-Actividad
17.
J Med Chem ; 55(5): 1844-57, 2012 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-22364417

RESUMEN

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC(50)s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC(50) = 15 nM PfNDH2; IC(50) = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED(50)/ED(90) of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc(1) complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.


Asunto(s)
Antimaláricos/síntesis química , Plasmodium falciparum/enzimología , Piridinas/síntesis química , Quinolonas/síntesis química , Quinona Reductasas/antagonistas & inhibidores , Administración Oral , Animales , Antimaláricos/química , Antimaláricos/farmacología , Atovacuona/farmacología , Cristalografía por Rayos X , Citocromos b/genética , Diseño de Fármacos , Resistencia a Medicamentos , Humanos , Malaria/tratamiento farmacológico , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Pruebas de Sensibilidad Parasitaria , Plasmodium berghei , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Piridinas/química , Piridinas/farmacología , Quinolonas/química , Quinolonas/farmacología , Ratas , Relación Estructura-Actividad
18.
PLoS One ; 6(6): e20101, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21698219

RESUMEN

BACKGROUND: Many captive chimpanzees (Pan troglodytes) show a variety of serious behavioural abnormalities, some of which have been considered as possible signs of compromised mental health. The provision of environmental enrichments aimed at reducing the performance of abnormal behaviours is increasing the norm, with the housing of individuals in (semi-)natural social groups thought to be the most successful of these. Only a few quantitative studies of abnormal behaviour have been conducted, however, particularly for the captive population held in zoological collections. Consequently, a clear picture of the level of abnormal behaviour in zoo-living chimpanzees is lacking. METHODS: We present preliminary findings from a detailed observational study of the behaviour of 40 socially-housed zoo-living chimpanzees from six collections in the United States of America and the United Kingdom. We determined the prevalence, diversity, frequency, and duration of abnormal behaviour from 1200 hours of continuous behavioural data collected by focal animal sampling. RESULTS, CONCLUSION AND SIGNIFICANCE: Our overall finding was that abnormal behaviour was present in all sampled individuals across six independent groups of zoo-living chimpanzees, despite the differences between these groups in size, composition, housing, etc. We found substantial variation between individuals in the frequency and duration of abnormal behaviour, but all individuals engaged in at least some abnormal behaviour and variation across individuals could not be explained by sex, age, rearing history or background (defined as prior housing conditions). Our data support a conclusion that, while most behaviour of zoo-living chimpanzees is 'normal' in that it is typical of their wild counterparts, abnormal behaviour is endemic in this population despite enrichment efforts. We suggest there is an urgent need to understand how the chimpanzee mind copes with captivity, an issue with both scientific and welfare implications.


Asunto(s)
Animales de Zoológico/psicología , Conducta Animal , Pan troglodytes/psicología , Animales , Estados Unidos
19.
Am J Phys Anthropol ; 142(3): 417-28, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20033921

RESUMEN

We analyzed patterns of paternity and male dominance rank in the Sonso community of wild East African chimpanzees (Pan troglodytes schweinfurthii) in the Budongo Forest, Uganda. Our major objective was to determine whether and how social rank influenced paternity success. We successfully genotyped 52 individuals at up to nine microsatellite loci, using DNA extracted from fecal samples. Of 24 offspring analyzed, we identified sires for 21. Paternity success was significantly correlated with social rank, with alpha males siring a disproportionate number of offspring. However, both middle- and low-ranking males also fathered offspring, and the priority-of-access model provided a relatively poor prediction of which males would be successful and under what circumstances. The concentration of paternities among only seven males and the tendency for high-ranking males to sire offspring of multiparous females suggest that both individual variation in male quality and the resource value of particular females may be mediating factors. In comparison with other chimpanzee studies, our results support the hypothesis that larger male cohort size reduces the ability of the alpha male to monopolize females, though within our study, male number did not affect the success of the alpha. Successful sires were not necessarily those who achieved the highest mating success with the females whose offspring they sired, but were those who demonstrated higher investment by spending significantly more time in association with these females. Finally, we estimate extra-group paternity at 0-5%, supporting other evidence that the community serves as the primary reproductive unit in chimpanzees.


Asunto(s)
Pan troglodytes/fisiología , Paternidad , Conducta Sexual Animal/fisiología , Predominio Social , Animales , Orden de Nacimiento , Femenino , Genotipo , Masculino , Repeticiones de Microsatélite , Pan troglodytes/genética , Estadísticas no Paramétricas , Árboles , Uganda
20.
Pers Soc Psychol Rev ; 13(2): 129-47, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19401595

RESUMEN

Social and personality psychology and behavioral primatology both enjoy long histories of research aimed at uncovering the proximate and ultimate determinants of primate-human and nonhuman-social behavior. Although they share research themes, methodologies, and theories, and although their studied species are closely related, there is currently very little interaction between the fields. This separation means that researchers in these disciplines miss out on opportunities to advance understanding by combining insights from both fields. Social and personality psychologists also miss the opportunity for a phylogenetic analysis. The time has come to integrate perspectives on primate social psychology. Here, the authors provide a historical background and document the main similarities and differences in approaches. Next, they present some examples of research programs that may benefit from an integrated primate perspective. Finally, the authors propose a framework for developing a social psychology inclusive of all primates. Such a melding of minds promises to greatly benefit those who undertake the challenge.


Asunto(s)
Etología/métodos , Personalidad , Primates , Psicología Social/métodos , Animales , Procesos de Grupo , Humanos , Modelos Psicológicos , Conducta Sexual , Conducta Sexual Animal , Terminología como Asunto
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