Interactions of Aurein with Model Membranes and Antimalarials

Aurein is a cationic antimicrobial peptide, rich in phenylalanine residues. Although the peptide has been extensively studied, its mechanism of action is not fully understood and has not been established. This project is focused on studying the interactions of aurein with model biological membranes and antimalarials using Fourier Transform Infrared (FTIR), fluorescence, dynamic light scattering (DLS), atomic force microscopy (AFM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) techniques. FTIR data revealed conformational changes to the secondary structure of the peptide in the presence of the model membranes. The strongest interactions of aurein were found with DOPC and lipid raft systems. Fluorescence data revealed some differences in the mechanism of interaction between aurein and lipid rafts. Topographical analysis was performed using atomic force microscopy (AFM). AFM images of the peptide with its lipid rafts showed a change in surface roughness suggesting a different mechanism of interaction. DLS data in agreement with FTIR confirmed that aurein interacts differently with the lipid rafts. The results gathered from this study provided new insights on the interaction of aurein. On the other hand, drug-drug interaction issues continue to present a major dilemma for the clinician caring for complex patients such as those infected with infectious disease. This study has examined the interaction of aurein with quinine, primaquine, and chloroquine. Significant interactions between aurein and antimalarials occured at a higher concentration of antimalarials. Interactions between aurein and anti-malarials reveal a strong interaction between aurein and primaquine. Interactions between aurein and quinine or chloroquine were found to be weak and negligible. FTIR, TGA, and DSC may be used in a complementary way to gain insights into the possible drug-drug interactions involving aurein. These studies are needed to initiate in vivo controlled interaction studies between antibiotics and antimalarials.

Regioselective Synthesis and Biological Evaluation of 1-Hydroxyl Modified Ailanthinone Derivatives as Antimalarials

The triterpene quassinoid ailanthinone is a structurally intricate natural product possessing highly potent antimalarial activity against multidrug resistance plasmodium parasites. Although the mechanism of action of ailanthinone is not completely understood, it is presumed to disrupt regular ribosomal functions by inhibiting parasite protein synthesis. Natural scarcity and low solubility of many quassinoids have impeded their development as potential clinical candidates, but exquisite potency of ailanthinone against Plasmodium remains compelling in the global fight against malaria. Herein, we report the highly selective synthesis of 1-hydroxyl derivatives of ailanthinone, including ester, carbonate, carbamate and sulfonate derivatives. The key feature of the synthesis is a one-step regioselective modification of the 1-hydroxyl group in favor of two other hydroxyl groups at C12 and C13. Derivatives were obtained via direct reaction with acyl/sulfonyl chlorides in the presence of a tertiary amine base without any protection-deprotection. In vitro antimalarial evaluations of these derivatives were compared with chloroquine and mefloquine against the Plasmodium falciparum clones, D6, W2, and TM91C235. The results demonstrate that modification of the 1-hydroxyl group is achievable, and the antimalarial activity of these derivatives relative to the parent product is significantly retained, thus paving the way for synthesis of derivatives with improved biological availability and/or increased potency.

Comparative effects of parenteral antimalarials in Swiss albino mice after chronic exposure to Plasmodium berghei

Mice are considered to be a similar model to humans in the pathogenesis of malaria. This study evaluates the effect of parenteral antimalarials on the spleen and liver of Swiss albino mice after chronic exposure to Plasmodium berghei. After chronic exposure to P. berghei NK65 strain, the level of parasitemia was assessed.The mice were treated for 3 days using chloroquine(5 mg/kg), quinine(10 mg/kg),and artemether(2 mg/kg). The effect of chronic exposure and the pattern of recovery were evaluated. There was significant decrease in total body weight after chronic exposure to P. berghei(P < 0.05). An increase in total weight recovery was seen after day 15 of treatment with the antimalarials; this was more pronounced with artemether. A significant increase in liver and spleen weights due to P. berghei infection was seen. There was a recovery pattern due to decrease in liver and spleen weights following antimalarial administration, which was greatest with artemether(P < 0.05). Significant changes were more in parasitized, quinine and artemether groups(P < 0.05). There was a significant decrease in total spleen protein due to chloroquine but a decrease due to quinine and artemether(P < 0.05). No significant changes in liver and spleen albumin were observed after treatment. The highest parasite clearance was observed with artemether, followed by quinine. Five mice died after chronic exposure in all the groups prior to treatment. There was significant enlargement and discoloration of spleen and liver after chronic exposure. This study showed that artemether aided recovery of the liver and spleen better than quinine and chloroquine in albino mice after chronic exposure to P. berghei. This suggests there is potential for improvement in antimalarial therapy.

Quality Control of Selected Antimalarials Sold in the Illicit Market: An Investigation Conducted in Porto-Novo City (Republic of Benin)

Malaria is a parasitic disease caused by the bite of female Anopheles mosquito and particularly affects the tropical areas of the world. According to national statistics it is the leading cause of consultations and hospitalizations. Nowadays, despite the surveillance systems for efficient malaria control and access to generic drugs, Benin is witnessing an increased development of illicit drug markets with a large part of the population going towards such markets. However, this is not without adverse impact on the health of individuals, as well as, the economic status of the country. Therefore, the situation needs to be seriously considered by policy makers at various levels, health professionals but also the entire international community in order to thwart this scourge.Regarding the aforementioned situation, the current study was undertaken aiming to perform a quality control of selected antimalarial drugs of the illegal market in Porto-Novo city. Therefore, 40 antimalarial batches were randomly collected in the illicit drug market and submitted to analytical tests such as: macroscopic examination (a visual and critical examination);mass uniformity test;disintegration test;identification test and active ingredients’ content measurement. At the end of the study, the percentages of non-compliance is 97.5%, 5%, 15% and 27.5%, respectively for the content uniformity tests, disintegration, identification and assay. Over-all, 42.5% of noncompliance was recorded. The findings of this study prove that street vended drugs offer no guarantee of good quality and pose a threat to the health of populations. Also, the rate of non-compliance denotes a flaw in the security of the drug distribution system.

Design,synthesis,and biological evaluation of multiple targeting antimalarials

Malaria still threatens global health seriously today.While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors,multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance.Here,we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule,RYL-581,which binds to multiple protein binding sites of P.falciparum simultaneously(allosteric site of type Ⅱ NADH dehydrogenase,Q_(o) and Q_(i) sites of cytochrome bc_(1)).Antimalarials with such multiple targeting mechanism of action have never been reported before.RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity.This structurebased strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future,especially for drug discovery on membrane-associated targets.

Availability of Antimalarial Medicines in Community Pharmacies of Lusaka District, Zambia: Implications on Compliance to Malaria Treatment Guidelines

Background: Malaria remains a major cause of morbidity and mortality in Zambia, affecting all levels of society, with children under the age of five and pregnant women being most at risk of serious illness. The availability of antimalarial medicines is one of the key interventions of malaria management. This study assessed the availability of antimalarial medicines in community pharmacies in Lusaka district, Zambia. Materials and Methods: This was a cross-sectional study that was conducted among 210 community pharmacies from September to November 2022 using a well-structured checklist in selected areas of Lusaka district. The availability was verified by a physical check of the product. The checklist contained the medicines listed both in the guidelines for diagnosis and treatment of malaria in Zambia as well as in the World Health Organization (WHO) malaria treatment guidelines. Results: This study found that all antimalarials listed in the local treatment guidelines for malaria were available in community pharmacies, though with the varying distribution. Of the 210 community pharmacies, 209 (99.5%) had artemether/lumefantrine in stock. The lowest available antimalarial was quinine/clindamycin, which was only available in 3 (1.4%) of the outlets. Conversely, 3 out of 16 (18.8%) antimalarials that were available in community pharmacies were not listed in the local treatment guidelines of malaria in Zambia, despite being listed in the WHO malaria treatment guidelines. This translated into a compliance level of 81.2% based on the local malaria treatment guidelines. Conclusion: This study concluded that antimalarials were available for all categories of malaria management in community pharmacies, though with a varying distribution. The presence of antimalarials not listed in the Zambian treatment guidelines is of public health concern which may have an impact on antimicrobial resistance in the future.

An updated study of traditional medicines to the era of 1,3,4 oxadiazole derivatives for malaria treatment

Discovering potent drug candidates requires new antimalarial targets.For this reason,antimalarial drug researchers focus on developing new drug candidates on promising targets.In the identification of these targets,a basic understanding of the metabolism and biochemical processes of malaria parasites such as Plasmodium falciparum can prove invaluable.However,malarial resistant parasites are becoming more and more significant issues as antimalarial medications progress.Antimalarial drugs are becoming increasingly resistant,thus the search for new molecules is very important task.Artemisinin based combination therapies are becoming more popular for treating malaria.This will ultimately lead to the selection of resistance due to their extensive and indiscriminate deployment.Alternative artemisinin-based combination therapies are therefore required.There is an interest in finding suitable antimalarial compounds based on their potential effectiveness against malaria.The potential activity of 1,3,4 oxadiazole analogues against malarial infections is a major draw of the search for suitable antimalarial compounds.This review identifies existing antimalarial drugs that have own therapeutic effects and evaluating their feasibility for developing novel synthetic antimalarial derivatives.

Designing Artemisinins with Antimalarial Potential, Combining Molecular Electrostatic Potential, Ligand-Heme Interaction and Multivariate Models

Artemisinins tested against W-2 strains of malaria falciparum are investigated with molecular electrostatic potential (MEP), in an attempt to identify key features of the compounds that are necessary for their activities, as well as to investigate likely interactions with the receptor in a biological process and to use that information to propose new molecules. In order to discover the best geometry involving the ligand-receptor complexes (heme) studied and help in the proposition of the new derivatives, molecular simulations of interactions between the most negative charged region around the peroxide and heme locates (the ones around the Fe2+ ion) were carried out. In addition, PCA (principal components analysis), HCA (hierarchical cluster analysis), SDA (stepwise discriminant analysis), and KNN (K-nearest neighbor) multivariate models were employed to investigate which descriptors are responsible for the classification between the higher and lower antimalarial activity of the compounds, and also this information was used to propose new potentially active molecules. The information accumulated in studies of MEP, molecular docking, and multivariate analysis supported the proposal of new structures with potential antimalarial activities. The multivariate models constructed were applied to the new structures and indicated numbers 19 and 20 as the most prominent for syntheses and biological assays.

Design of N-11-Azaartemisinins Potentially Active against Plasmodium falciparum by Combined Molecular Electrostatic Potential, Ligand-Receptor Interaction and Models Built with Supervised Machine Learning Methods

N-11-azaartemisinins potentially active against Plasmodium falciparum are designed by combining molecular electrostatic potential (MEP), ligand-receptor interaction, and models built with supervised machine learning methods (PCA, HCA, KNN, SIMCA, and SDA). The optimization of molecular structures was performed using the B3LYP/6-31G* approach. MEP maps and ligand-receptor interactions were used to investigate key structural features required for biological activities and likely interactions between N-11-azaartemisinins and heme, respectively. The supervised machine learning methods allowed the separation of the investigated compounds into two classes: cha and cla, with the properties εLUMO+1 (one level above lowest unoccupied molecular orbital energy), d(C6-C5) (distance between C6 and C5 atoms in ligands), and TSA (total surface area) responsible for the classification. The insights extracted from the investigation developed and the chemical intuition enabled the design of sixteen new N-11-azaartemisinins (prediction set), moreover, models built with supervised machine learning methods were applied to this prediction set. The result of this application showed twelve new promising N-11-azaartemisinins for synthesis and biological evaluation.

A retrospective evaluation of the quality of malaria case management at twelve health facilities in four districts in Zambia

Objective:To establish the appropriateness of malaria case management at health facility level in four districts in Zambia.Methods:This study was a retrospective evaluation of the quality of malaria case management at health facilities in four districts conveniently sampled to represent both urban and rural settings in different epidemiological zones and health facility coverage.The review period was from January to December 2008.The sample included twelve lower level health facilities from four districts.The Pearson Chi-square test was used to identify characteristics which affected the quality of case management.Results:Out of 4891 suspected malaria cases recorded at the 12 health facilities,more than 80%of the patients had a temperature taken to establish their fever status.About 67%(CI_(95)66.1-68.7)were tested for parasitemia by either rapid diagnostic test or microscopy,whereas the remaining22.5%(CI_(95)213.1-23.7)were not subjected to any malaria test.Of the 2247 malaria cases reported(complicated and uncomplicated),71%were parasitologicaily confirmed while 29%were clinically diagnosed(unconfirmed).About 56%.(CI_(95)53.9-58.1)of the malaria cases reported were treated with artemether-lumefantrine(AL),35%(CI_(95)33.1-37.0)with sulphadoxine-pyrimethamine,8%(CI_(95)6.9-9.2)with quinine and 1%did not receive any anti-malarial.Approximately 30%of patients WHO were found negative for malaria parasites were still prescribed an anti-malarial,contrary to the guidelines.There were marked inter-district variations in the proportion of patients in WHOm a diagnostic tool was used,and in the choice of anti-malarials for the treatment of malaria confirmed cases.Association between health worker characteristics and quality of case malaria management showed that nurses performed better than environmental health technicians and clinical officers on the decision whether to use the rapid diagnostic test or not.Gender,in service training on malaria,years of residence in the district and length of service of the health worker at the facility were not associated with diagnostic and treatment choices.Conclusions:Malaria case management was characterised by poor adherence to treatment guidelines.The non-adherence was mainly in leans of:inconsistent use of confirmatory tests(rapid diagnostic test or microscopy)for malaria;prescribing anti-malarials which are not recommended(e.g.sulphadoxine-pyrimethamine)and prescribing anti-malarials to cases testing negative.Innovative approaches are required to improve health worker adherence to diagnosis and treatment guidelines.

Profiling of seminal antioxidant indices and sperm quality in Plasmodium bergheiinduced malarial mice treated with Phyllanthus amarus

Objective:To evaluate the antiplasmodial activity of Phyllanthus(P.)amarus crude ethanol leaf extract and its effects on semen quality in male BALB/c mice.Methods:A total of 36 adult mice were divided into six groups,with 6 mice each.Five groups were infected with Plasmodium(P.)berghei,and one group was left uninfeceted.Of the five infected groups,one group was left untreated,three groups were treated with varying doses(100,250 and 400 mg/kg)of P.amarus crude ethanol leaf extract orally for 4 days,and another group was treated with standard drug,artemether and lumefantrine(Lonart®DS).Antiplasmodial activity,seminal quality,some biochemical indices(neutral毩-glucosidase,fructose,and citric acid)in seminal plasma and seminal antioxidant markers(catalase,glutathione peroxidase,reduced glutathione,malondialdehyde,total antioxidant capacity,and acid phosphates)were determined.The mice were euthanized 3 days post treatment and semen was collected from the caudal epididymis and processed for analysis using documented methods and procedures.Results:Malarial infection led to oxidative stress,causing a significant decline in seminal quality(P<0.05).However,treatment with P.amarus crude ethanol leaf extract alleviated oxidative stress and significantly improved seminal quality.The improvement was dose-dependent and compared well with the standard drug,artemether and lumefantrine(Lonart®DS)treatment.Conclusions:The ethanol leaf extracts of P.amarus alleviate male reproductive capacity during malaria infection in murine model by enhancing antioxidant activities.

青蒿素之母——2015年诺贝尔生理学或医学奖新科得主屠呦呦(二)

2015年10月5日,中国中医科学院(原中国中医研究院)终身研究员兼首席研究员、女药学家、药物化学家、医学家和教育家屠呦呦以创制新型抗疟药物——青蒿素及其首个衍生物双氢青蒿素而赢得当年诺贝尔生理学或医学奖之殊荣,特大喜讯传来,国内舆论媒体亢奋,国人无不欢欣鼓舞。屠呦呦先生是首位荣获诺贝尔科学奖的中国大陆本土科学家、首位华裔女性诺奖得主和诺医奖得主,这是中国医学界尤其是中医学界的重大历史性突破,这一荣耀将永远铭记在中国科技发展史上。详细介绍了屠呦呦女士的生平、主要学术成就与贡献、与疟疾直接相关的诺医奖以及青蒿素类抗疟药物获得的各种国内外奖项,简明扼要地阐述了青蒿素类抗疟药物的发现(发明)简史,不惜浓墨重彩全方位地展示了以屠呦呦为杰出代表的中国科学家群英谱的奋斗历程和辉煌成就。

青蒿素之母——2015年诺贝尔生理学或医学奖新科得主屠呦呦(一)

2015年10月5日,中国中医科学院(原中国中医研究院)终身研究员兼首席研究员、女药学家、药物化学家、医学家和教育家屠呦呦以创制新型抗疟药物——青蒿素及其首个衍生物双氢青蒿素而赢得当年诺贝尔生理学或医学奖之殊荣,特大喜讯传来,国内舆论媒体亢奋,国人无不欢欣鼓舞。屠呦呦先生是首位荣获诺贝尔科学奖的中国大陆本土科学家、首位华裔女性诺奖得主和诺医奖得主,这是中国医学界尤其是中医学界的重大历史性突破,这一荣耀将永远铭记在中国科技发展史上。详细介绍了屠呦呦女士的生平、主要学术成就与贡献、与疟疾直接相关的诺医奖以及青蒿素类抗疟药物获得的各种国内外奖项,简明扼要地阐述了青蒿素类抗疟药物的发现(发明)简史,不惜浓墨重彩全方位地展示了以屠呦呦为杰出代表的中国科学家群英谱的奋斗历程和辉煌成就。

青蒿素之母——2015年诺贝尔生理学或医学奖新科得主屠呦呦(四)

2015年10月5日,中国中医科学院(原中国中医研究院)终身研究员兼首席研究员、女药学家、药物化学家、医学家和教育家屠呦呦以创制新型抗疟药物——青蒿素及其首个衍生物双氢青蒿素而赢得当年诺贝尔生理学或医学奖之殊荣,特大喜讯传来,国内舆论媒体亢奋,国人无不欢欣鼓舞。屠呦呦先生是首位荣获诺贝尔科学奖的中国大陆本土科学家、首位华裔女性诺奖得主和诺医奖得主,这是中国医学界尤其是中医学界的重大历史性突破,这一荣耀将永远铭记在中国科技发展史上。详细介绍了屠呦呦女士的生平、主要学术成就与贡献、与疟疾直接相关的诺医奖以及青蒿素类抗疟药物获得的各种国内外奖项,简明扼要地阐述了青蒿素类抗疟药物的发现(发明)简史,不惜浓墨重彩全方位地展示了以屠呦呦为杰出代表的中国科学家群英谱的奋斗历程和辉煌成就。

青蒿素之母——2015年诺贝尔生理学或医学奖新科得主屠呦呦(三)

2015年10月5日,中国中医科学院(原中国中医研究院)终身研究员兼首席研究员、女药学家、药物化学家、医学家和教育家屠呦呦以创制新型抗疟药物——青蒿素及其首个衍生物双氢青蒿素而赢得当年诺贝尔生理学或医学奖之殊荣,特大喜讯传来,国内舆论媒体亢奋,国人无不欢欣鼓舞。屠呦呦先生是首位荣获诺贝尔科学奖的中国大陆本土科学家、首位华裔女性诺奖得主和诺医奖得主,这是中国医学界尤其是中医学界的重大历史性突破,这一荣耀将永远铭记在中国科技发展史上。详细介绍了屠呦呦女士的生平、主要学术成就与贡献、与疟疾直接相关的诺医奖以及青蒿素类抗疟药物获得的各种国内外奖项,简明扼要地阐述了青蒿素类抗疟药物的发现(发明)简史,不惜浓墨重彩全方位地展示了以屠呦呦为杰出代表的中国科学家群英谱的奋斗历程和辉煌成就。

Chemotherapy and drug resistance status of malaria parasite in northeast India

India reports the highest number of malaria cases in Southeast Asia,of which Plasmodium falciparum contribute more than half of the cases every year.North eastern states of India contribute only 3.96%of country’s population but account for】10%of total reported malaria cases.11%of Plasmodium falciparum cases and 20%of malaria related deaths annually.In India,chloroquine resistance was reported for the first time from northeast region and since then chloroquine treatment failure is being reported from many parts of the region.Increased chloroquine treatment failure has led to change of the drug policy to artemisinin combination therapy as first line of malaria treatment in the region.However,replacing chloroquine to artemisinin combination therapy has not shown significant difference in the overall malaria incidence in the region,The present review addresses the current malaria situation of northeastern region of India in the light of antimalarials drug resistance.

Current and emerging trends in antimalarial drugs:a comprehensive review

Malaria is a ubiquitous tropical disease which occurs by the bite of malaria parasite of genus Plasmodium spp.The procurement and treatment of malaria depend on the cost and emergence of drug resistance,chemical compositions of drug molecules,and different complications and toxic effects associated with them.The antimalarials are classified as gametocidal,prophylaxis,blood schizonticides,tissue schizonticides and sporontocides.In addition,new antimalarial drugs have been discussed in the present review that offers the advantage singly or in combination with other drugs.The ridiculous vector control methods,appearance of drug-resistant parasites,and deficiency of effective vaccines against malaria are the main aspects responsible for the expansion of malaria.Hence,the development of a new drug is the need of hour to conquer the clinical failures of traditional chemotherapy.Though,the discovery and development of a new drug is a costly and lengthy process,hence different nanotechnological techniques may recommend hopeful approaches for the procurement of malaria amid minimum side effects.Delivery of traditional anti-malarial drugs in nanoform offers an opportunity to improve their therapeutic efficacy,reduced side-effects by targeted delivery and improved patient's compliance.This review article will critically highlight the different traditional,hybrid and new anti-malarial drugs.Moreover,different nanocarriers discovered for the site specific liberation of antimalarials to enhance the therapeutic efficiency of these drugs have been comprehensively discussed in this review.

Malaria parasite carbonic anhydrase:inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

Plasmodium falciparum(P.falciparum) is responsible for the majority of life-threatening cases of human malaria,causing 1.5-2.7 million annual deaths.The global emergence of drug-resistant malaria parasites necessitates identification and characterisation of novel drug targets and their potential inhibitors.We identified the carbonic anhydrase(CA) genes in P.falciparum.The pfGA gene encodes an α-carbonic anhydrase,a Zn^(2+)-metalloenzme,possessing catalytic properties distinct from that of the human host CA enzyme.The amino acid sequence of the pfCA enzyme is different from the analogous protozoan and human enzymes.A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions.The structure of the groups substituting the aromatic-ureido-or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides.One derivative,that is,4-(3,4-dichlorophenylureido)thioureidobcnzcnesulfonamide(compound 10) was the most effective in vitro Plasmodium falciparum CA inhibitor,and was also the most effective antimalarial compound on the in vitro P.falciparum growth inhibition.The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei,an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.

In vitro Potentiation of Antimalarial Activities by Daphnetin Derivatives Against Plasmodium falciparum

Objective To screen the antimalarial compounds of daphnetin derivatives against Plasmodium falciparum in vitro. Method Plasmodium faciparum （FCC1） was cultured in vitro by a modified method of Trager and Jensen. Antimalarial compounds were screened by microscopy-based assay and microfluorimetric method. Results DA79 and DA78 showed potent antimalarial activity against Plasmodiumfalciparum cultured in vitro. Conclusion Though the relationship between the structures of daphnetin derivatives and their antimalarial activities has not been clarified yet, this study may provide a new direction for discovery of more potential antimalarial compounds.

Putative metabolic roles of the mitochondria in asexual blood stages and gametocytes of Plasmodium falciparum

Upon infection into human red cell,Plasmodium falciparum differentiates into asexual and sexual(gametocyte) stages.The mitochondrion is a tubular-cristate organelle,functionally and structurally different between the two stages.Genes and proteins involving metabolic and functional roles,protein targeting and import to this organelle, are comprehensively reviewed.The genes and proteins of the electron transport system are identified, partially characterized in human and rodent malaria parasites consisting of a single subunit of NADH dehydrogenase, two subunits of succinate dehydrogenase,cytochrome C reductase and cytochrome Coxidase.One of the primary functional roles of the mitochondrion in the parasite is the coordination of pyrimidine biosynthesis, the electron transport system and oxygen utilization through dihydroorotate dehydrogenase.All enzymes of tricarboxylic acid cycle,pyruvate dehydrogenase complex and some enzymes of ATP synthase,are identified and partially characterized using the completed P.falciparum genome.Some metabolic and functional roles of the organelle include oxidative phosphorylation,ubiquinone and heme biosynthesis,antioxidant defense and redox balance.Recent physiological studies involve membrane potential maintenance,cellular signaling and cation homeostasis.The organelle is a target for antimalarial drug,i.e.atovaquone.Based on the lines of evidence, we hypothesize that the parasite exhibits metabolic adaptation of the underdeveloped mitochondrial organelle to life in the mosquito vector and the human host.