Computational Analysis of Physicochemical, Pharmacokinetic and Toxicological Properties of Deoxyhypusine Synthase Inhibitors with Antimalarial Activity

Malaria is a parasitic disease which has as etiological agents protozoa of the genus Plasmodium prevalent in tropical countries. The appearance of Plasmodium strains resistant to artemisinin has become necessary the development of new drugs using computational tools to combat this epidemic. Diverse transporter proteins can act as antimalarials targets, thereby being the enzyme deoxyhypusine synthase a promising antimalarial target. The present study aimed to investigate 15 most active inhibitors of deoxyhypusine synthase target, deposited in databases Binding DB, in order to trace a pattern of physicochemical, pharmacokinetic and toxicological properties of the inhibitors for this enzyme and propose new inhibitors of deoxyhypusine synthase target. The physicochemical properties were obtained according to the Lipinski parameters to evaluate oral absorption. Based on the certain properties were proposed three new inhibitors (A, B and C). The ADME/Tox properties were calculated for new inhibitors compared with results of the selected compounds. The fifteen inhibitors for oral administration showed satisfactory results, because they have adapted to the Lipinski parameters. In relation to the penetration of the blood-brain barrier the inhibitors analyzed showed penetration values less than 1, and ranged from 0.0411815 to 0.481764, being that the compound 1 showed value of CBrain/CBlood = 0.135467. Compound B showed a higher strength in plasma protein binding in relation to the compound 1, having a variation be-tween them of ±1.489344. Therefore, the compound B would present a longer halflife compared with compound 1. The proposed compounds showed positive and satisfactory results, being able to reach less adverse effects related to the central nervous system depending of administered dose.

SCREENING OF MEDICINAL PLANTS FROM REUNION ISLAND FOR ANTIMALARIAL ACTIVITY

According to the last World Malaria Report,there were an estimated 584 000 malaria deaths worldwide in 2013.The problem of parasite resistance towards available medicines is increasing.Natural products could play an important role to discover new antimalarial drug.The aim of the study was to highlight the anti-plasmodial properties of plants used in traditional medicine on the Mascarene Islands.85

Ethnobotanical survey of antimalarial plants in Awash-Fentale District of Afar Region of Ethiopia and in vivo evaluation of selected ones against Plasmodium berghei

Objective: To document plants used in traditional treatment of malaria in the Awash-Fentale District, the Afar Region of Ethiopia, and to evaluate antimalarial activity of selected ones against Plasmodium berghei in mice. Methods: Semi-structured interviews were carried out with purposively selected informants in the District to gather information on plants used in the traditional treatment of malaria. Standard procedures were used to investigate acute toxicity and a four-day suppressive effect of crude aqueous and ethanol extracts of the leaves of the two most frequently cited plants [Aloe trichosantha(A. trichosantha) and Cadaba rotundifolia(C. rotundifolia)] against Plasmodium berghei in Swiss albino mice. Results: The informants cited a total of 17 plants used in the traditional treatment of malaria in Awash-Fentale District. Plant parts were prepared as infusions or decoctions. Leaf was the most commonly cited(44%) plant part, followed by stem(22%). Shrubs were the most frequently cited(63%) medicine source followed by trees(21%). Of the 17 plants, C. rotundifolia and A. trichosantha were the most frequently mentioned plants in the district. Ethanol extracts of the leaves of C. rotundifolia and A. trichosantha suppressed P. berghei parasitaemia significantly accounting for 53.73% and 49.07%, respectively at 900 mg/kg. The plants were found to be non-toxic up to a dose of 1 500 mg/kg. Conclusions: Seventeen plant species were reported to be used for treatment of malaria in the Awash Fentale Distinct, among which A. trichosantha and C. rotundifolia were the most preferred ones. P. berghei suppressive activity of these plants may partly explain their common use in the community.

ATP gatekeeper of Plasmodium protein kinase may provide the opportunity to develop selective antimalarial drugs with multiple targets

Malaria is one of the most devastating infectious diseases that caused millions of clinical cases annually despite decades of prevention efforts. Recent cases of Plasmodium falciparum resistance against the only remaining class of effective antimalarial(artemisinin) in South East Asia may soon pose a significant threat. Hence, the identification of new antimalarial compounds with a novel mode of action is necessary to curb this problem. Protein kinase has been implicated as a valid target for drug development in diseases such as cancer and diabetes in humans. A similar approach is now recognized for the treatment of protozoan-related disease including malaria. Few Plasmodium protein kinases that are not only crucial for their survival but also have unique structural features have been identified as a potential target for drug development. In this review, studies on antimalarial drug development exploiting the size of Plasmodium protein kinase ATP gatekeeper over the past 15 years are mainly discussed. The ATP-binding site of Plasmodium protein kinases such as Pf CDPK1, Pf CDPK4, Pf PKG, Pf PK7, and Pf PI4K showed great potential for selective and multi-target inhibitions owing to their smaller or unique ATP-gatekeeper amino acid subunits compared to that of human protein kinase. Hence it is a feasible solution to identify a new class of active antimalarial agents with a novel mode of action and longer clinical life-span.

A New Antimalarial Noreudesmane Sesquiterpenoid from Dobinea delavayi

One previously undescribed angeloylated noreudesmane sesquiterpenoid,dobinin O(1),along with four known eudesmane sesquiterpenoids(2-5)were isolated from the peeled roots of Dobinea delavayi.Their structures were elucidated by extensive spectroscopic data analyses.In addition,compound 1 exhibited moderate antimalarial activity against Plasmodium yoelii BY265RFP with the inhibition ratio of 17.8±13.3%at the dose of 30 mg/kg/day.

Comparative Investigation of QHS and DQHS with Density Functional Theory

The electronic structures of QHS and DQHS were completely optimized and calculated by B3LYP density functional theory at the 6-31g* level. The relationship between electronic structure parameters and antimalarial activity was discussed. There exists significant difference in frontier orbitals of QHS and DQHS. Their net charges and bond orders were also compared respectively. The results of calculation prove theoretically that the endoperoxy bridge is the essential of antimalarial activity. The difference of antimalarial activity between QHS and DQHS was reasonably explained based on their electronic structures.

Furoquinoline Alkaloids and Methoxyflavones from the Stem Bark of Melicope madagascariensis(Baker)T.G.Hartley

Melicope madagascariensis(Rutaceae)is an endemic plant species of Madagascar that was first classified as a member of the genus Euodia J.R.&G.Forst(Rutaceae)under the scientific name Euodia madagascariensis Baker.Based on morphological characteristics,Thomas Gordon Hartley taxonomically revised E.madagascariensis Baker to be M.madagascariensis(Baker)T.G.Hartley.Chemotaxonomical studies have long been used to help the identification and confirmation of taxonomical classification of plant species and botanicals.Aiming to find more evidences to support the taxonomical revision performed on E.madagascariensis,we carried out phytochemical investigation of two samples of the plant.Fractionation of the ethanol extracts prepared from two stem bark samples of M.madagascariensis(Baker)T.G.Hartley led to the isolation of seven known furoquinoline alkaloids 1–7 and two known methoxyflavones 8 and 9.The presence of furoquinoline alkaloids and methoxyflavones in the title species is in agreement with its taxonomic transfer from Euodia to Melicope.Antiprotozoal evaluation of the isolated compounds showed that 6-methoxy-7-hydroxydictamnine(heliparvifoline,3)showed weak antimalarial activity(IC_(50)=35μM)against the chloroquine-resistant strain Dd2 of Plasmodium falciparum.Skimmianine(4)displayed moderate cytotoxicity with IC_(50)value of 1.5 lM against HT-29 colon cancer cell line whereas 3,5-dihydroxy-30,40,7-trimethoxyflavone(9)was weakly active in the same assay(IC_(50)=13.9μM).

Antimalarial and neuroprotective ent-abietane diterpenoids from the aerial parts of Phlogacanthus curviflorus

Six new ent-abietane diterpenoids,abientaphlogatones A−F(1−6),along with two undescribed ent-abietane diterpenoid glucosides,abientaphlogasides A−B(7−8)and four known analogs were isolated from the aerial parts of Phlogacanthus curviflorus(P.curviflorus).The structures of these compounds were determined using high-resolution electrospray ionization mass spectrometry(HR-ESI-MS),one-dimensional and two-dimensional nuclear magnetic resonance(NMR)spectroscopy,electronic circular dichroism(ECD)spectra,and quantum chemical calculations.Notably,compounds 5 and 6 represented the first reported instances of entnorabietane diterpenoids from the genus Phlogacanthus.In theβ-hematin formation inhibition assay,compounds 2,4,7−10,and 12 displayed antimalarial activity,with IC_(50) values of 12.97−65.01μmol·L−1.Furthermore,compounds 4,5,8,and 10 demonstrated neuroprotective activity in PC12 cell injury models induced by H_(2)O_(2) and MPP+.

Design,synthesis and in vitro evaluation of tetrahydropyrimidine-isatin hybrids as potential antitubercular and antimalarial agents

A series of 5-substituted-3-[{5-（6-methyl-2-oxo/thioxo-4-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl）-1,3,4-oxadiazol-2-yl}-imino] -1,3-dihydro-2H-indol-2-one were synthesized,characterized and screened for their anti-tubercular and antimalarial activity.

Crystal habit,characterization and pharmacological activity of various crystal forms of arteether

The aim of this study was to investigate and characterize different crystal forms of arteether,a rapidly acting,highly potent antimalarial drug for the treatment of acute Plasmodium falciparum malaria.Six different crystal forms were prepared utilizing various polar and non-polar solvents.Scanning electron microscopy(SEM)revealed differences in the surface characteristics of the six forms from those of a commercial sample.Differential scanning calorimetry(DSC)revealed the absence of a desolvation endotherm indicating that the forms were neither hydrates nor solvates.Powder X-ray diffraction(PXRD)patterns of the forms showed much weaker major peaks than in the commercial sample indicating them to be less crystalline.Solubility and dissolution studies showed that the most amorphous form was the most soluble and possessed the highest antimalarial activity.

Two Terpenoid Derivatives with Different 3/5/6/6/5-Fused Pentacyclic Skeletons from Hedyosmum orientale

Chemical investigation of Hedyosmum orientale led to the identification of two terpenoid derivatives,dyosmunoids A and B(1 and 2)featuring two different 3/5/6/6/5-fused pentacyclic ring systems,respectively.Compound 1 is the second natural product of this C_(25) terpenoid compound class,and compound 2 is a rare dinor-C25 terpenoid with a peroxide bridge.Their structural elucidation was achieved by the comprehensive analysis of spectroscopic data,single-crystal X-ray diffraction,and ECD calculation.Putative biosynthetic pathways for compounds 1 and 2 are proposed.Compound 2 exhibited strong antimalarial activity with an IC_(50) value of 0.42μmol·L^(-1).

Cipaferoids A-C, Three Limonoids Represent Two Different Scaffolds from Cipadessa baccifera

Three limonoids cipaferoids A-C （1-3） representing two different scaffolds were isolated from Cipadessa baccifera. Their structures were completely assigned by spectroscopic data, CD exciton chirality method, and X-ray crystallography. Compounds 2 and 3 exhibited moderate antimalarial activity with IC50 values of 9.3±0.1 and 14.7±4.8 μmol·L^-1, respectively.

Cephalotane-Type Norditerpenoids from Cephalotaxus fortunei var.alpina

A chemical investigation of the 95%EtoH extract of the seeds of Cephalotaxus fortunei var.alpina led to the isolation of nine new cephalotane-type norditerpenoids,ceforalides A-I(1-9),and two known analogues(10 and 11).Compounds 1-8 belong to a rare class of A-ring-contracted cephalotane-type norditerpenoids,of which compound 8 incorporates a unique tetrasubstituted 2,5-cyclohexadienone A-ring.Compound 9 is a rare 13,14-seco-17-nor-cephalotane-type diterpenoid.Their structures were determined based on NMR,HRESIMS,ECD,and X-ray diffraction analysis.Biological tests revealed compounds 10 and 11 displayed moderate antimalarial activity.