Cardioprotective effects of the aqueous extract of Echinops cephalotes on myocardial ischemia-reperfusion in rats by modulation of MMP-2, MMP-9, TIMP, and oxidative stress.

Echinops plants have received great attention for the treatment of many diseases due to pharmacological properties such as their antidiabetic, antioxidant, and anti-inflammatory characteristics. The major purpose of the present study was to investigate the cardioprotective benefits of Echinops cephalotes (Ech) against myocardial ischemia-reperfusion (MI/R) injury. Male Wistar rats were randomly allocated to three groups: sham, MI, and MI + Ech. The left coronary artery (LAD) was blocked for 30 minutes to induce MI. In the treatment group, rats were given 150 mg/kg/day of Ech extract for 28 days. Aqueous extracts were made from Echinops plants. To study heart function, fibrosis, cardiac damage indicators, and oxidative stress factors, echocardiography, Masson's trichrome staining, and biochemical tests were used. The expression of matrix metalloproteinase 2 and 9 (MMP2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP) was determined using Western blotting. Tissue damage was assessed using hematoxylin and eosin staining. MI group exhibited significantly reduced ejection fraction (EF) and fractional shortening (FS), enhanced levels of lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), cardiac Troponin I (cTnI), and malondialdehyde (MDA), as well as a decrease in the Glutathione (GSH) tissue content, reduced activity of superoxide dismutase (SOD), increasing fibrosis, upregulations of MMP-2 and MMP-9, and reduction of TIMP compared to the sham group. The findings suggest that Ech in particular, could be a promising therapeutic agent to reduce the damage in MI by targeting oxidative stress and modulating the activities of matrix metalloproteinases and their tissue inhibitors.

Click chemistry beyond metal-catalyzed cycloaddition as a remarkable tool for green chemical synthesis of antifungal medications.

Click chemistry is widely used for the efficient synthesis of 1,4-disubstituted-1,2,3-triazole, a well-known scaffold with widespread biological activity in the pharmaceutical sciences. In recent years, this magic ring has attracted the attention of scientists for its potential in designing and synthesizing new antifungal agents. Despite scientific and medical advances, fungal infections still account for more than 1.5 million deaths globally per year, especially in people with compromised immune function. This increasing trend is definitely related to a raise in the incidence of fungal infections and prevalence of antifungal drug resistance. In this condition, an urgent need for new alternative antifungals is undeniable. By focusing on the main aspects of reaction conditions in click chemistry, this review was conducted to classify antifungal 1,4-disubstituted-1,2,3-triazole hybrids based on their chemical structures and introduce the most effective triazole antifungal derivatives. It was notable that in all reactions studied, Cu(I) catalysts generated in situ by the reduction in Cu(II) salts or used copper(I) salts directly, as well as mixed solvents of t-BuOH/H2O and DMF/H2O had most application in the synthesis of triazole ring. The most effective antifungal activity was also observed in fluconazole analogs containing 1,2,3-triazole moiety and benzo-fused five/six-membered heterocyclic conjugates with a 1,2,3-triazole ring, even with better activity than fluconazole. The findings of structure-activity relationship and molecular docking of antifungal derivatives synthesized with copper-catalyzed azide-alkyne cycloaddition (CuAAC) could offer medicinal chemistry scientists valuable data on designing and synthesizing novel triazole antifungals with more potent biological activities in their future research.

In vitro and in vivo antiplasmodial activity of a synthetic dihydroartemisinin-eosin B hybrid.

With the inexorable prevalence and spread of drug-resistant malaria strains, many efforts have been made to find alternative chemotherapeutic agents. In this regard, scientists have developed the concept of hybridization of two or more active pharmacophores into a single chemical compound, resulting in "antimalarial hybrids." The aim of this study was planned based on the highly synergistic effect of the physical hybrid of dihydroartemisinin (DHA) with eosin B (EB). Therefore, a chemical hybrid of the two compounds (DHA-EB) was synthesized, and its antimalarial activity was investigated in vitro and in vivo. The drug hybrid was fabricated through a propionyl ester linker between DHA and EB. The antiplasmodial activity of the new hybrid was tested in vitro on the blood stages of Plasmodium falciparum (chloroquine-sensitive, 3D7 strain) and also evaluated in vivo by Peters' standard test in mice infected with Plasmodium berghei. The hybrid compound was also assessed for in vivo toxicity. Among all the compounds studied, a DHA-EB hybrid showed an appropriate inhibition percentage (53%) was at a very low dose (0.65 nM). The highest in vivo antimalarial activity until the 9th day was related to DHA-EB in a low dose (0.5 mg/kg). Also, the most survival rate was observed in the test group of hybrid compound at a dose of 1.5 mg/kg for 22 days. No external changes were identified in the toxicity assay. The weight of internal organs of treated animals and that of controls indicated nontoxicity of DHA-EB even after 60 days of consumption. In vitro and in vivo studies substantiated that DHA-EB hybrid has the potential for developing as a safe antimalarial drug.

Evaluation of Anti-Bacterial and Anti-Biofilm Activity of Native Probiotic Strains of Lactobacillus Extracts.

Background: Lactic acid bacteria produce various beneficial metabolites, including antimicrobial agents. Owing to the fast-rising antibiotic resistance among pathogenic microbes, scientists are exploring antimicrobials beyond antibiotics. In this study, we examined four Lactobacillus strains, namely L. plantarum 42, L. brevis 205, L. rhamnosus 239, and L. delbrueckii 263, isolated from healthy human microbiota, to evaluate their antibacterial and antifungal activity. Methods: Lactobacillus strains were cultivated, and the conditioned media were obtained. The supernatant was then used to treat pathogenic bacteria and applied to the growth media containing fungal and bacterial strains. Additionally, the supernatant was separated to achieve the organic and aqueous phases. The two phases were then examined in terms of bacterial and fungal growth rates. Disk diffusion and MIC tests were conducted to determine strains with the most growth inhibition potential. Finally, the potent strains identified through the MIC test were tested on the pathogenic microorganisms to assess their effects on the formation of pathogenic biofilms. Results: The organic phase of L. rhamnosus 239 extracts exhibited the highest antibacterial and antibiofilm effects, while that of L. brevis 205 demonstrated the most effective antifungal impact, with a MIC of 125 µg/mL against Saccharomyces cerevisiae. Conclusion: This study confirms the significant antimicrobial impacts of the lactic acid bacteria strains on pathogenic bacteria and fungi; hence, they could serve as a reliable alternative to antibiotics for a safe and natural protection against pathogenic microorganisms.

Anti-mosquito properties of Pelargonium roseum (Geraniaceae) and Juniperus virginiana (Cupressaceae) essential oils against dominant malaria vectors in Africa.

BACKGROUND: More than 90% of malaria cases occur in Africa where the disease is transmitted by Anopheles gambiae and Anopheles arabiensis. This study evaluated the anti-mosquito properties of Juniperus virginiana (JVO) and Pelargonium roseum (PRO) essential oils (EOs) against larvae and adults of An. gambiae sensu lato (s.l.) from East Africa in laboratory and semi-field conditions. METHODS: EOs was extracted from the aerial green parts of Asian herbs by hydrodistillation. Their constituents were characterized by gas chromatography-mass spectrometry (GC-MS). Larvicidal activities of JVO, PRO, and PRO components [citronellol (CO), linalool (LO), and geraniol (GO)] were investigated against An. gambiae sensu stricto (s.s.). The percentage of knockdown effects and mortality rates of all oils were also evaluated in the adults of susceptible An. gambiae s.s. and permethrin-resistant An. arabiensis. RESULTS: GC-MS analyses identified major constituents of JVO (sabinene, dl-limonene, ß-myrcene, bornyl acetate, and terpinen-4-ol) and PRO (citronellol, citronellyl formate, L-menthone, linalool, and geraniol). Oils showed higher larvicidal activity in the laboratory than semi-field trials. The LC50 values for JVO/PRO were computed as 10.82-2.89/7.13-0.9 ppm and 10.75-9.06/13.63-8.98 ppm in laboratory and semi-field environments, respectively at exposure time of 24-72 h. The percentage of knockdown effects of the oils were also greater in An. gambiae s.s. than in An. arabiensis. Filter papers impregnated with JVO (100 ppm) and PRO (25 ppm) displayed 100% mortality rates for An. gambiae s.s. and 3.75% and 90% mortality rates, for An. arabiensis populations, respectively. Each component of CO, LO, and GO exhibited 98.13%, 97.81%, and 87.5%, respectively, and a mixture of the PRO components indicated 94.69% adult mortality to permethrin-resistant An. arabiensis. CONCLUSIONS: The findings of this study show that PRO and its main constituents, compared to JVO, have higher anti-mosquito properties in terms of larvicidal, knockdown, and mortality when applied against susceptible laboratory and resistant wild populations of An. gambiae s.l. Consequently, these oils have the potential for the development of new, efficient, safe, and affordable agents for mosquito control.

Robust antibacterial activity of functionalized carbon nanotube- levofloxacine conjugate based on in vitro and in vivo studies.

A new nano-antibiotic was synthesized from the conjugation of multi-walled carbon nanotubes with levofloxacin (MWCNT-LVX) through covalent grafting of drug with surface-modified carbon nanotubes in order to achieve an effective, safe, fast-acting nano-drug with the minimal side effects. This study is the first report on the evaluation of in vitro cell viability and antibacterial activity of nano-antibiotic along in addition to the in vivo antibacterial activity in a burn wound model. The drug-loading and release profile at different pH levels was determined using an ultraviolet-visible spectrometer. MWCNT-LVX was synthesized by a simple, reproducible and cost-effective method for the first time and characterized using various techniques, such as scanning electron microscope, transmission electron microscopy, and Brunauer-Emmett-Teller analysis, and so forth. The noncytotoxic nano-antibiotic showed more satisfactory in vitro antibacterial activity against Staphylococcus aureus compared to Pseudomona aeruginosa. The novel synthetic nano-drug possessed high loading capacity and pH-sensitive release profile; resultantly, it exhibited very potent bactericidal activity in a mouse S. aureus wound infection model compared to LVX. Based on the results, the antibacterial properties of the drug enhanced after conjugating with surface-modified MWCNTs. The nano-antibiotic has great industrialization potential for the simple route of synthesis, no toxicity, proper drug loading and release, low effective dose, and strong activity against wound infections. In virtue of unique properties, MWCNTs can serve as a controlled release and delivery system for drugs. The easy penetration to biological membranes and barriers can also increase the drug delivery at lower doses compared to the main drug alone, which can lead to the reduction of its side effects. Hence, MWCNTs can be considered a promising nano-carrier of LVX in the treatment of skin infections.

Synthesis and biological activity profile of novel triazole/quinoline hybrids.

Based on the significant and diverse pharmacophore features of triazole ring and considering the potent antimicrobial properties of quinoline scaffold, a novel series of 1,2,3-triazole-based polyaromatic compounds containing chloroquinoline moiety were synthesized through a well-established synthetic methodology, named click chemistry. The structure of the synthetic compounds was characterized by various spectroscopic methods. The final products of triazole/quinoline hybrids and ((prop-2-yn-1-yloxy)methyl)benzene intermediates were screened for their antibacterial (Staphylococcus aureus, Escherichia coli, Shigella flexneri, and Salmonella enterica), antifungal (Candida albicans, Saccharomyces cerevisiae, and Aspergillus fumigatus), and cytotoxic activities. The best antifungal compounds exhibited minimum inhibitory concentration (MIC), in the range of 0.35-0.63 µM, against S. cerevisiae without any cytotoxic effect. These compounds can be selected as the potential candidates for treating invasive fungal infections caused by S. cerevisiae, after further investigation. Preliminary in silico ADME studies also predicted the favorable pharmacokinetic attributes of most compounds.

Phytochemical Composition and Bioassay on Iranian Teucrium Polium Extracts against Anopheles Stephensi (Diptera: Culicidae).

Background: Anopheles stephensi is an important malaria vector mosquito in Iran and other western Asian countries. In many human communities, plant products have been used traditionally instead of synthetic pesticides for mosquito control due to their minimal hazardous effects. Teucrium polium, known popularly as felty germander, has been introduced in Persian Medicine (PM) as an insect repellent from a long time ago. Methods: The present study was undertaken to evaluate repellent and larvicidal activity of dichloromethane (DCMETP) and ethanolic extracts (EE-TP) of T. polium against An. stephensi under laboratory conditions. The possible chemical components of the extracts were also investigated through gas chromatography/mass spectrometry (GC-MS) technique. Results: Based on the results, DCME-TP showed better repellent activity than EE-TP with 56.67 and 28.33 % protection, respectively. Larvicidal activity of DCME-TP with 49.41% mortality was also higher than EE-TP (20.24%). The main identified constituents of DCME-TP were long chain alkanes, phenol, aromatic ester, oxaspiro and triterpenoid. While phenolic and aliphatic acid were only the identified components in EE-TP. It is notable that lupeol was detected in DCME of T. polium for the first time. Conclusion: DCME-TP can be considered as a new herbal candidate to control An. stephensi mosquitoes. Further studies are required on this extract for the fractionation and identification of the active compounds, and the evaluation of their bioactivity in the laboratory and field.

Nature׳s gifts to medicine: The metabolic effects of extracts from cocoons of Larinus hedenborgi (Coleoptera: Curculionidae) and their host plant Echinops cephalotes (Asteraceae) in diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Trehala manna (TM), the edible cocoons of several weevil species, e.g. Larinus hedenborgi Boheman, 1845 (Coleoptera: Curculionidae) and their host plant, i.e. Echinops cephalotes DC. (EC) (Asteraceae), are traditionally used to treat pain, inflammation, infectious diseases, as well as respiratory, renal, reproductive and metabolic disorders. AIM OF THE STUDY: This study investigated the metabolic effects of aqueous extracts from TM and EC on diabetic male Wistar albino rats. MATERIALS AND METHODS: Animals were orally gavaged with the extracts (75, 150, and 300 mg/kg), normal saline, and glibenclamide (Glbn), for 28 days. The serum levels of glucose, insulin, lipid profile, and hepatic enzymes, plus the body weight of rats were measured at the beginning and the end of study. The proximate composition of the extracts was determined, additionally. The antioxidant and cytotoxic potency of the extracts were evaluated by radical scavenging/ferric reducing and viability assays, respectively. RESULTS: Treatment of diabetic rats with the extracts significantly altered metabolic biomarkers compared with diabetic, control and Glbn-treated groups, but not in a dose-dependent manner. However, the antihyperglycemic effects of TM75/EC300, the antiobesity effects of EC150, and the hepatoprotective effects of TM150/EC150 were even stronger than those of Glbn. TM/EC-treated groups represented normal cell architecture in the pancreatic and renal tissues. Nutrient analysis displayed that TM is rich in sugar and magnesium, whereas EC is abundant in protein, sodium, potassium, and calcium. The extracts showed no antioxidant and cytotoxic effects, as compared to the control groups. CONCLUSIONS: The findings suggest that active ingredients in the extracts evaluated are responsible for the metabolic effects by lowering blood sugar and restoring the damaged islets of Langerhans. The close trophic relationship of the TM-producing beetle with the host thistle justifies the overlaps of the bioactivity of the TM and EC extracts.

Bioactivities of rose-scented geranium nanoemulsions against the larvae of Anopheles stephensi and their gut bacteria.

Anopheles stephensi with three different biotypes is a major vector of malaria in Asia. It breeds in a wide range of habitats. Therefore, safer and more sustainable methods are needed to control its immature stages rather than chemical pesticides. The larvicidal and antibacterial properties of the Pelargonium roseum essential oil (PREO) formulations were investigated against mysorensis and intermediate forms of An. stephensi in laboratory conditions. A series of nanoemulsions containing different amounts of PREO, equivalent to the calculated LC50 values for each An. stephensi form, and various quantities of surfactants and co-surfactants were developed. The physical and morphological properties of the most lethal formulations were also determined. PREO and its major components, i.e. citronellol (21.34%), L-menthone (6.41%), linalool (4.214%), and geraniol (2.19%), showed potent larvicidal activity against the studied mosquitoes. The LC50/90 values for mysorensis and intermediate forms were computed as 11.44/42.42 ppm and 12.55/47.69 ppm, respectively. The F48/F44 nanoformulations with 94% and 88% lethality for the mysorensis and intermediate forms were designated as optimized formulations. The droplet size, polydispersity index, and zeta-potential for F48/F44 were determined as 172.8/90.95 nm, 0.123/0.183, and -1.08/-2.08 mV, respectively. These results were also confirmed by TEM analysis. Prepared formulations displayed antibacterial activity against larval gut bacteria in the following order of decreasing inhibitory: LC90, optimized nanoemulsions, and LC50. PREO-based formulations were more effective against mysorensis than intermediate. Compared to the crude PREO, the overall larvicidal activity of all nanoformulations boosted by 20% and the optimized formulations by 50%. The sensitivity of insect gut bacteria may be a crucial factor in determining the outcome of the effect of toxins on target insects. The formulations designed in the present study may be a good option as a potent and selective larvicide for An. stephensi.

In silico and in vivo anti-malarial investigation on 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine derivatives.

BACKGROUND: Resistance of Plasmodium falciparum against common anti-malarial drugs emphasizes the need of alternative and more effective drugs. Synthetic derivatives of 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine have showed in vitro anti-plasmodial activities. The present study aimed to evaluate the molecular binding and anti-plasmodial activity of synthetic compounds in vivo. METHODS: The molecular docking was used to study the binding of compounds to haem and Plasmodium falciparum lactate dehydrogenase (PfLDH). Acute toxicity of the synthetic compounds was evaluated based on the modified up & down method. The anti-plasmodial activity of the compounds was conducted by the two standard tests of Peters' and of Rane, using chloroquine-sensitive Plasmodium berghei in mice. Also, the toxicity to the internal organs of mice was evaluated on the seventh day after the treatment in addition to the histopathology of their liver. Compound 3 that showed high activity in the lowest dose was selected for further pharmacodynamic studies. RESULTS: According to the docking studies, the active site of PfLDH had at least four common residues, including Ala98, Ile54, Gly29, and Tyr97 to bind the compounds with the affinity, ranging from - 8.0 to - 8.4 kcal/mol. The binding mode of ligands to haem revealed an effective binding affinity, ranging from - 5.1 to - 5.5 kcal/mol. Compound 2 showed the highest  % suppression of parasitaemia (99.09%) at the dose of 125 mg/kg/day in Peters' test. Compound 3, with 79.42% suppression, was the best in Rane's test at the lowest dose (31 mg/kg/day). Compound 3 was confirmed by the pharmacodynamic study to have faster initial parasite elimination in the lowest concentration. The histopathology of the livers of mice did not reveal any focal necrosis of hepatocytes in the studied compounds. CONCLUSIONS: The docking studies verified Pf LDH inhibition and the inhibitory effect on the haemozoin formation for the studied compounds. Accordingly, some compounds may provide new avenues for the development of anti-malarial drugs without liver toxicity, although further studies are required to optimize their anti-plasmodial activity.

Synthesis of novel amodiaquine analogs and evaluation of their in vitro and in vivo antimalarial activities.

BACKGROUND & OBJECTIVES: Due to the rapid increase of drug resistance in Plasmodium parasites, there is a pressing need of developing new antiplasmodial drugs. In this study, new amodiaquine (AQ) analogs were synthesized, followed by an evaluation of their antiplasmodial activity. METHODS: A new series of quinoline derivatives containing N-alkyl (piperazin-1-yl)methyl benzamidine moiety was synthesized by reacting 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzonitrile with appropriate primary amines. The synthesized compounds were investigated for inhibitory activity by inhibition test of heme detoxification (ITHD). Their antiplasmodial activity was then evaluated using the classical 4-day suppressive test (Peter's test) against Plasmodium berghei-infected mice (ANKA strain). RESULTS: The results showed that the percentage of heme detoxification inhibition in the active compounds was 90%. The most promising analogs, N-butyl-4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl]benzamidine (compound 1e), and 4-[(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)]-N-(4-methylpentan-2-yl)benzamidine (compound 1f) displayed 97.65 and 99.18% suppressions at the doses of 75 and 50 mg/kg/day, respectively. Further, the mean survival time of the mice treated with these compounds was higher than that of the negative control group. INTERPRETATION & CONCLUSION: The newly synthesized amodiaquine analogs presented sufficient antiplasmodial activity with excellent suppressions and high in vitro heme detoxification inhibition. Higher mean survival time of the mice treated with synthetic compounds further confirmed the in vivo antimalarial activity of these new AQ analogs. Therefore, these compounds have the potential to replace common drugs from 4-aminoquinoline class. However, further investigations such as pharmacokinetic evaluations, cytotoxicity, toxicity, and formulation seem to be necessary.

GC-MS analysis and anti-mosquito activities of Juniperus virginiana essential oil against Anopheles stephensi (Diptera: Culicidae)

Objective: To investigate phytochemicals present in the essential oil from aerial parts of eastern red cedar, Juniperus virginiana (J. virginiana) L. (Cupressaceae) and to determine its killing and repellent activities against larvae, pupae, and adults of the Asian malaria mosquito,Anopheles stephensi (Diptera: Culicidae).Methods: J. virginiana essential oil was extracted by hydrodistillation, and its chemical composition was determined by gas chromatography-mass spectrometry. Seven different logarithmic concentrations of J. virginiana essential oils were used in larvicidal and pupicidal assays. J. virginiana essential oils-impregnated bed nets were applied in a designed animal module to test excito-repellent activity against adult mosquitoes.Results: Fourteen constituents corresponding to 99.98％ of J. virginiana essential oils were identified. Five main components were terpinen-4-ol (25.21％), camphor (19.89％), E-3-hexen- 1-ol (13.30％), γ-terpinene (7.86％), and l-menthone (2.27％). The LC50 and LC90 values against larvae of the Anopheles stephensi were 11.693 and 66.140 ppm and for pupae were 9.640 and 40.976 ppm, respectively. In excito-repellency assay, J. virginiana essential oilsimpregnated bed nets provided an average of 54.63％ protection for guinea pig and 45.37％ mortality for the mosquitoes. Conclusions: Four monoterpenes and one leaf alcohol were identified by gas chromatographymass spectrometry. J. virginiana essential oils showed potent larvicidal, pupicidal, adulticidal,and repellent activities against Anopheles stephensi at acceptable concentrations. Evaluation of bioactivity of identified chemicals (alone or in combination) will provide new eco-friendly substances for mosquito-management programs.

Synthesis and antiplasmodial activity of novel phenanthroline derivatives: An in vivo study.

OBJECTIVES: Due to the rapid increased drug resistance to Plasmodium parasites, an urgent need to achieve new antiplasmodial drugs is felt. Therefore, in this study, the new synthetic phenanthroline derivatives were synthesized with antiplasmodial activity. MATERIALS AND METHODS: A series of 1,10-phenanthroline derivatives containing amino-alcohol and amino-ether substituents were synthesized via facile procedures, starting with 5,6-epoxy-1,10-phenanthroline. Their antiplasmodial activity was then evaluated using Peter's 4-day suppressive test against Plasmodium berghei-infected mice (ANKA strain). Furthermore, the mean survival time of the mice treated with synthetic compounds was compared with the negative control group. RESULTS: The results demonstrated that the compounds 6-(3-(dibutylamino)propylamino)-5,6-dihydro-1,10-phenanthroline-5-ol(7b) at the dose of 150 mg/kg/day and 4-(1,10-phenanthroline-5-yloxy)-N, N-dipropylbutan-1-amine (8b) at the dose of 15 mg/kg/day have 90.58% and 88.32% suppression, respectively. All synthetic compounds prolonged the mean survival time of treated mice in comparison with negative control groups, indicating the in vivo antiplasmodial activity of these new compounds. CONCLUSION: The present study is the first attempt to achieve new, effective synthetic compounds based on phenanthroline scaffold with the antiplasmodial activity. However, more research is needed to optimize their antimalarial activity.

Chemical Composition and Antimicrobial Activities of Iranian Propolis

Background: With considering the importance of natural products for their remedial and therapeutic value, this research was aimed to analyze the chemical compositions and antimicrobial activity of four propolis samples from different areas of Iran (Chenaran, Taleghan, Morad Beyg, and Kalaleh) with various climates and flora. Methods: Ethanolic (70% EtOH) and dichlromethane (DCM) extracts of Iranian propolis were analyzed by gas chromatography-mass spectrometry (GC-MS) methods, and antimicrobial activity was evaluated against Candida albicans, Escherichia coli, and Staphylococcus aureus using disk diffusion antimicrobial method. Results: The results of GC-MS analysis showed the presence of fatty acids, flavonoids, terpenes, aromatic-aliphatic acids, and their related esters. The total flavonoids in DCM extract of Chenaran, Taleghan, Morad Beyg, and Kalaleh propolis were pinocembrin and pinostrobin chalcone. The common phenolic and terpene compounds detected in all four tested EtOH extracts were P-cumaric acid and dimethyl -1,3,5,6-tetramethyl-[1,3-(13C2)] bicycloce [5.5.0] dodeca-1,3,5,6,8,10-hexaene-9,10-dicarboxylate, respectively. The highest inhibitory diameter zone of the Iranian propolis against C. albicans, E. coli, and S. aureus was for DCM extract of Kalaleh propolis (13.33 mm), Morad Beyg propolis (12 mm), and Kalaleh (11.67 mm), respectively. Conclusion: Iranian propolis showed antimicrobial activities against C. albicans, E. coli, and S. aurous, perhaps due to the presence of flavonoids, phenolic acids, and terpenes as active components that can be used alone or in combination with the selected antibiotics to synergize antibiotic effect, as well as to prevent microbial resistance to available antimicrobial drugs.

Synthesis and Comparison of In Vitro Leishmanicidal Activity of 5-(Nitroheteroaryl)-1,3,4-Thiadiazols Containing Cyclic Amine of Piperidin-4-ol at C-2 with Acyclic Amine Analogues against Iranian Strain of Leishmania major (MRHO/IR/75/ER).

BACKGROUND: Cutaneous Leishmaniasis (CL) is endemic in many tropical and subtropical regions of the world. Due to the prolonged duration of therapy, adverse effect and resistance to current drugs in the treatment of CL, the discovery of novel, efficient, and safe leishmanicidal drugs is required. The aims of the present study was to synthesis of new compounds based on the active compounds of 5-(5-nitrofuran-2-yl)- and 5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazole bearing the linear amino alcohol of 3-aminopropan-1-ol in the C-2 position of thiadiazole ring and evaluation of their activity against the promastigote and amastigote forms of Leishmania major. METHODS: Reaction between the solution of 5-(5-nitro heteroaryl)-2-chloro-1,3,4-thiadiazole and piperidin-4-ol in absolute ethanol was performed and the resulting products were evaluated against promastigotes form of L. major with MTT assay and amastigote form of L. major in murine peritoneal macrophages. In addition, the toxicity of these compounds was assessed against mouse peritoneal macrophages with MTT assay. RESULTS: New synthetic compounds 5a-b showed moderate in vitro antileishmanial activity against L. major promastigotes with IC50 values of 68.9 and 27µM, respectively. These compounds have also demonstrated a good antiamastigote activity in terms of amastigote number per macrophage, the percentage of macrophage infectivity and infectivity index. CONCLUSION: Novel cyclic compounds 5a-b were synthesized and exhibited less antipromastigote and antiamastigote activity compared to linear analogues.

Thiadiazoles: the appropriate pharmacological scaffolds with leishmanicidal and antimalarial activities: a review.

Leishmaniasis and malaria are serious public health problems in tropical and sub-tropical regions worldwide. Development of drug-resistant strains has disrupted efforts to control the spread of these diseases in the world. The conventional antiparasitic chemotherapy still suffers from side effects and drug resistance. Therefore, the development of novel antimalarial and leishmanicidal drugs remains a critical topic to combat against these diseases. Five-membered heterocyclic systems have possessed antiparasitic activity such as thiadiazole scaffold which is a prevalent and an important heterocyclic ring. For this purpose, the authors introduce a series of synthetic thiadiazole derivatives with antileishamanial activity. Also, the authors searched a number of sources and articles to find thiadiazole derivatives with antileishamnial and antimalarial activity. Then all of the findings were reviewed. 5-nitroheteroaryl-1,3,4-Thiadiazole derivatives with different substituents at position 2 of the thiadiazole ring (8, 10-11) presented the best antileishmanial activity with low toxicity compared with reference drug. Also, 1,3,4-thiadiazole-2-sulfonamide derivative (18) showed excellent inhibitory activity against pfCA as a special enzyme in Plasmodium falciparum. Thiadiazole scaffold has the suitable physicochemical and pharmacokinetic properties and still stays as a therapeutic target for the development of a novel lead in the medicinal chemistry. Therefore, the current review provides a brief summary of medicinal chemistry of thiadiazole ring and introduces novel leads possessing this nucleus with antimalarial and antileishmanial activities.

Anti-Plasmodial Assessment of Four Different Iranian Propolis Extracts.

BACKGROUND: Eradication of malaria will depend on discovery of new intervention tools such as anti-malarial drugs. Due to the increasing interest in the application of propolis against significant clinical pathogenic agents, the aim of the present investigation was to evaluate the anti-plasmodial effect of Iranian propolis extracts against chloroquine (CQ)-sensitive Plasmodium falciparum 3D7 and Plasmodium berghei (ANKA strain). METHODS: Crude samples of honeybee (Apis mellifera) propolis were collected from four provinces in northern (Kalaleh, Golestan), northeastern (Chenaran, Razavi Khorasan), central (Taleghan, Alborz) and western (Morad Beyg, Hamedan) areas of Iran with different types of flora. The dried propolis samples were extracted with three different solvents, including ethanol 70% (EtOH), ethyl acetate (EA) and dichloromethane (DCM). RESULTS: All extracts were shown to have in vitro anti-plasmodial activity with IC50 ranging from 16.263 to 80.012 µg/mL using parasite lactate dehydrogenase (pLDH) assay. The DCM extract of Morad Beyg propolis indicated the highest anti-plasmodial activity (IC50: 16.263 ± 2.910 µg/mL; P = 0.027, Kruskal-Wallis H-test). The samples were also evaluated in mice for their in vivo anti-plasmodial effect. The curative effect against established infection (Rane test) showed that both extracts at all doses (50, 100, and 200 mg/kgBW) produced anti-plasmodial activity against the parasite. Furthermore, using gas chromatography-mass spectrometry (GC-MS), the quantity of flavonoids in DCM and EtOH 70% extracts were found to be 7.42% and 3.10%, respectively. CONCLUSION: The potent anti-plasmodial activity of both EtOH 70% and DCM extracts of the propolis of Morad Beyg, Hamedan suggests further analyses of individual components to assess its utilization as anti-malarial drugs.

Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine: A Narrative Review.

Antimalarial drugs with the 4-aminoquinoline scaffold such as the important drugs, chloroquine (CQ) and amodiaquine (AQ), have been used to prevent and treat malaria for many years. The importance of these drugs is related to their simple usage, high efficacy, affordability, and cost-effectiveness of their synthesis. In recent years, with the spread of parasite resistance to CQ and cross-resistance to its other analogues have decreased their consumption in many geographical areas. On the other hand, AQ is an effective antimalarial drug which its usage has been restricted due to hepatic and hematological toxicities. The significance of the quinoline ring at quinoline-based antimalarial drugs has prompted research centers and pharmaceutical companies to focus on the design and synthesis of new analogues of these drugs, especially CQ and AQ analogues. Accordingly, various derivatives have been synthesized and evaluated in vitro and in vivo against the resistant strains of the malaria parasite to solve the problem of drug resistance. Also, the pharmacokinetic properties of these compounds have been evaluated to augment their efficacy and diminish their toxicity. Some of these analogues are currently in clinical and preclinical development. Consequently, the recent researches showed yet 4-aminoquinoline scaffold is active moiety in new compounds with antiplasmodial activity. Hence, the aim of this review article is to introduce of the novel synthetic analogues of CQ and AQ, which may constitute the next generation of antimalarial drugs with the 4-aminoquinoline scaffold.

In vitro immunobiological studies of novel 5-(5-nitrofuran-2-yl)-1, 3, 4-thiadiazoles with piperazinyl-linked benzamidine substituents against Leishmania major.

It was recently demonstrated that 5-(5-nitrofuran-2-yl)-1, 3, 4-thiadiazoles with piperazinyl-linked benzamidine substituents are effective in vitro against Leishmania major.Following on this evidence, we used colorimetric assay of acid phosphatase activity in the promastigotes as an indicator for cell viability. Also we studied the effect of these compounds on induction of nitric oxide (NO) in macrophage and production of reactive oxygen species (ROS) in lymphocyte that have important role in activation of immune response against Leishmania and elimination of parasite.Results showed that these compounds decrease the viability of the parasite and increase ROS and NO production in lymphocyte and macrophage respectively.These compounds can induce parasite killing, directly by decreasing the parasite viability and indirectly by exhibiting a significant increase on immune system.