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• Synthesis of pyrazolo[5,1-b]quinazoline-3-carboxylate derivatives 4(a-u) via one-pot three-component reaction under microwave. • The low cost and reusability of PEG-400 make it an efficient solvent. • All the synthetics were evaluated for in vitro antimicrobial, antitubercular, and antimalarial, and Cytotoxicity activity. • Molecular docking study also streamlined the plausible binding interactions of compound 4 u and active site of DNA gyrase. • Most of the compounds showed positive results in drug-likeness properties and ADMET predictions. Herein, we explored an environmentally benign synthesis of pyrazolo[5,1- b ]quinazoline-3-carboxylate derivatives 4(a-u) as potential antimicrobial, antitubercular as well as antimalarial agents. Our approach employed microwave-assisted PEG-400 as a biodegradable reaction medium to expedite the one-pot fusion of 1,3-dicarbonyl compounds 1(a-c), substituted aldehyde s 2(a-g), and ethyl-3-aminopyrazole-4-carboxylate (3a). The current protocol offers the advantages of a low E-factor, high atom economy, mild reaction condition, reusability of PEG-400 and produce water as a byproduct with a favorable yield (up to 96 % yield) in a short reaction time. Compared to the MIC values of standard antibiotics against their respective strains, compound 4g exhibited superior activity against Bacillus subtilis while compound 4r demonstrated a more favorable MIC against Pseudomonas aeruginosa. Against Candida albicans, compounds 4c, 4f, 4i, 4o, 4r, and 4u showed excellent antifungal activity as compared standard medications griseofulvin and fluconazole. Compounds 4d and 4p showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv whereas compounds 4d, 4e, 4p and 4q showed good antimalarial activity against Plasmodium falciparum in contrast to standard drug ciprofloxacin and quinine respectively. In vitro cytotoxicity assay against S. pombe cells indicated that the majority of tested compounds exhibit more than 80 % cell viability, suggesting their non-toxic nature. A molecular docking study was conducted to elucidate the potential interactions between compound 4u and the active site of DNA gyrase. Based on the noteworthy findings from the investigation of drug-like properties and ADMET predictions, these derivatives depict an efficient multifunctional action and offer prospective access for future discoveries of antimicrobial, antitubercular, as well as antimalarial studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Chloroquine diphosphate (CHQ) is primarily used for the treatment of Plasmodium falciparum malaria at the dose of 500 mg orally or 10 mg/kg parenterally. However, point mutations in Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein and Plasmodium falciparum multidrug resistance protein 1 (Pfmdr1) localized in digestive vacuole membrane, are responsible for CHQ resistance. Therefore, in present investigation, dextran nanoparticles bearing chloroquine diphosphate (CHQ-DEX-NPs) were formulated by solvent diffusion method of size below 70 nm with zeta-potential of −20.1 ± 3.2 mV. FT-IR, DSC and PXRD techniques confirmed the successful loading of drug in nanomatrix system with amorphous attributes. In vitro drug release analysis indicated the Higuchi pattern with diffusion controlled drug release. The IC 50 of CHQ-DEX-NPs in sensitive (3D7) and resistant (RKL9) Plasmodium falciparum strains was estimated to be 0.031-μg/ml and 0.13-μg/ml significantly lower than 0.059-μg/ml and 0.36-μg/ml of CHQ. The augmented therapeutic efficacy of CHQ-DEX-NPs may be credited to deposition of tailored nanoparticles in food vacuoles of malaria parasites owing to the affinity of parasite towards DEX that consequently lower the drug resistance and improved the therapeutic index. In conclusion, CHQ-DEX-NPs must be evaluated under a set of stringent in vivo parameters to establish its therapeutic efficacy in preclinical model. [ABSTRACT FROM AUTHOR]

Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biológica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P. berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanácea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9μg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of Costa Rica. Rev. Biol. Trop. 60 (2): 881-891. Epub 2012 June 01.El tratamiento con las drogas antimaláricas de uso común han inducido resistencia por parte del parásito, lo que obliga a buscar en las plantas de los bosques, componentes naturales con actividad en contra de esta enfermedad. Por lo tanto, decidimos buscar dichos componentes en plantas de una Reserva Forestal de Costa Rica. Extractos tanto frescos como secos de raíz, corteza, hojas, flores y frutos, de 25 plantas de la Reserva Biológica Alberto Manuel Brenes (REBAMB), fueron estudiados in vitro en busca de sustancias con actividad antimalárica. Las plantas estudiadas fueron: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) y Myriocarpa longipes (Urticaceae). Los extractos frescos y secos de las diferentes partes de las plantas fueron estudiadas y se determinó la IC50, el cual osciló entre 1-71.9mg/mL; los extractos frescos mostraron mayor actividad antimalárica. Las plantas que presentaron mayor actividad son muy comunes en Centroamérica y algunos géneros similares, aunque no las mismas especies, han sido encontrados positivos en América del Sur; por esta razón consideramos importante estos resultados como información y materia de discusión en este tema. Además este es el primer estudio sistemático de esta naturaleza realizado en un área boscosa circunscrita y protegida de Costa Rica.

A new series of chloroquinoline-4 H -chromene conjugates incorporating piperizine or azipane tethers were synthesized and their anti-malarial activity were evaluated against two Plasmodium falciparum strains namely 3D7 chloroquine sensitive (CQS) and K1 chloroquine resistant (CQR). Chloroquine was used as the standard and also reference for comparison. The conjugates exhibit intense UV absorption with λ max located at 342 nm (log ε = 4.0), 254 nm (log ε = 4.2), 223 nm (log ε = 4.4) which can be used to spectrometrically track the molecules even in trace amounts. Among all the synthetic compounds, two molecules namely 6-nitro and N -piperazine groups incorporated 7d and 6-chloro and N -azapane incorporated 15b chloroquinoline-4 H -chromene conjugates showed significant anti-malarial activity against two strains (3D7 and K1) of P. falciparum . These values are lesser than the values of standard antimalarial compound. Molecular docking results suggested that these two compounds showing strong binding affinity with P. falciparum lactate dehydrogenase (PfLDH) and also they occupy the co-factor position which indicated that they could be the potent inhibitors for dreadful disease malaria and specifically attack the glycolytic pathway in parasite for energy production. [ABSTRACT FROM AUTHOR]

Chemical investigation of the organic extract obtained from the sponge Plakortis simplex collected in the South China Sea afforded five new polyketide endoperoxides ( 2 and 4 – 7 ), along with two known analogues ( 1 and 3 ). The stereostructures of these metabolites have been deduced on the basis of spectroscopic analysis and chemical conversion. The isolated endoperoxide derivatives have been tested for their in vitro antimalarial activity against Plasmodium falciparum strains, showing IC 50 values in the low micromolar range. The structure–activity relationships were analyzed by means of a detailed computational investigation and rationalized in the light of the mechanism of action proposed for this class of simple antimalarials. The relative orientation of the atoms involved in the putative radical generation and transfer reaction was demonstrated to have a great impact on the antimalarial activity. The resulting 3D pharmacophoric model can be a useful guide to design simple and effective antimalarial lead compounds belonging to the class of 1,2-dioxanes. [ABSTRACT FROM AUTHOR]

Abstract: This paper reports on the syntheses and spectrometric characterisation of eleven novel ent-kaurane diterpenoids, including a complete set of 1H, 13C NMR and crystallographic data for two novel ent-kaurane diepoxides. Moreover, the antineoplastic cytotoxicity for kaurenoic acid and the majority of ent-kaurane derivatives were assessed in vitro against a panel of fourteen cancer cell lines, of which allylic alcohols were shown to be the most active compounds. The good in vitro antimalarial activity and the higher selectivity index values observed for some ent-kaurane epoxides against the chloroquine-resistant W2 clone of Plasmodium falciparum indicate that this class of natural products may provide new hits for the development of antimalarial drugs. [Copyright &y& Elsevier]

Treatment with the usual antimalarial drugs, have induced parasite resistance, reinforcing the need to finding natural antimalarial components that would be found on plants from the forest. Therefore, we decided to look for these components in Costa Rican plants from a protected forest area. Fresh and dry extracts of roots, bark, leaves, flowers and fruits of 25 plants from a biological reserve in Costa Rica, Reserva Biológica Alberto Manuel Brenes (REBAMB), were studied in vitro for the presence of substances with antimalarial activity. By studying the inhibition of P. berghei schizogony, we assessed the antimalarial activity of several plant extracts: Aphelandra aurantiaca, A. tridentata (Acanthaceae); Xanthosoma undipes (Araceae); Iriartea deltoidea (Arecaceae); Neurolaena lobata (Asteraceae); Senna papillosa, Pterocarpus hayessi, Lonchocarpus pentaphyllus (Fabaceae); Nectandra membranacea, Persea povedae, Cinamomum chavarrianum (Lauraceae); Hampea appendiculata (Malvaceae); Ruagea glabra, Guarea glabra (Meliaceae); Psidium guajava (Myrtaceae); Bocconia frutescens (Papaveraceae); Piper friedrichsthalii (Piperaceae); Clematis dioica (Ranunculaceae); Prunus annularis (Rosaceae); Siparuna thecaphora (Siparunaceae); Solanum arboreum, Witheringia solanacea (Solanaceae); Ticodendrum incognitum (Ticodendraceae); Heliocarpus appendiculatus (Tiliaceae) and Myriocarpa longipes (Urticaceae). We used different parts of the plants as well as fresh and dried extracts for testing IC50. The solid content of the extracts ranged from 1-71.9μg/mL. The fresh extracts showed stronger activity than the dry ones. Since the plants showing the strongest antimalarial activity are very common in Central America, and some similar genera of these plants have shown positives results in South America, we considered important to present these findings for discussion. On the other hand, this is the first systematic study of this kind ever realized in a circumscribed and protected area of Costa Rica. [ABSTRACT FROM AUTHOR]

Several new chalcone analogues were synthesized and evaluated as inhibitors of malaria parasite. Inhibitory activity was determined in vitro against a chloroquine-sensitive Plasmodium falciparum strain of parasites. The compound 3-(4-methoxyphenyl)-1-(4-pyrrol-1-yl-phenyl)prop-2-en-1-one was found to be the most active with 50% inhibition concentration (IC50) of 1.61 μg/ml. This inhibitory concentration is comparable to a prototype phytochemical chalcone, licochalcone A, with an IC50 of 1.43 μg/ml. The present study suggests that small, lipophilic nitrogen heterocyclic ring A together with small hydrophobic functionality at ring B can enhance antimalarial activity. These results suggest that chalcones are a class of compounds that provides an option of developing inexpensive, synthetic therapeutic antimalarial agents in the future. Claisen-Schmidt condensation method was employed to synthesize various substituted chalcones. Among all, 3-(4-Methoxyphenyl)-1-(4-pyrrol-1-yl-phenyl)prop-2-en-1-one was found to be most effective with IC50 value of 1.6 μg/ml in vitro against chloroquine sensitive strain (3D7) of Plasmodium falciparum. [ABSTRACT FROM AUTHOR]