Hybrid Compounds as Direct Multitarget Ligands: A Review de Oliveira Pedrosa, Michelle; Duarte da Cruz, Rayssa Marques; de Oliveira Viana, Jessika ...
Current topics in medicinal chemistry,
04/2017, Volume:
17, Issue:
9
Journal Article
Peer reviewed
Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single ...molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years.
The genus Cissampelos comprises of 21 species which have a wide global distribution and various pharmacological activities such as analgesic and antipyretic, antiinflammatory, anti-allergic, ...bronchodilation, and immunomodulation among others. Several compounds, mainly alkaloids with differing biological activities have been isolated from this genus. We will highlight antipyretic activities, anti-inflammatory, antiallergic, bronchodilatory, and immunomodulatory activities. In addition, we applied ligand-based-virtual screening associated with structure-based-virtual screening of a small dataset of 63 secondary metabolites from the Cissampelos genus of an in-house data bank, in order to select compounds with potential anti-inflammatory activity. Affinities were observed for hayatine (26), isochondrondendrine (30), pelosine (52), sepeerine (59), and warifteine (63) to the inhibiting enzymes MAPK p38 alpha, PKC beta, PKC theta and PKC zeta. The cissampeloflavone compound (8) alone showed no potential inhibitory activity for PKC zeta, or affinity for the PKC alpha. The compounds can be used as starting points for further studies on structures with potential anti-inflammatory activity.
A study with the yellow passion fruit peel flour showed positive action in blood glucose control as therapies' adjuvant in patients with type 2 diabetes mellitus. Therefore, we evaluated its effect ...on insulin sensitivity since there is a quest for studies that focus at better understanding of insulin resistance aspects in diabetic patients. Furthermore its relationship with chronic complications can also give good prospects for alternative treatments.
A total of 43 type 2 diabetes volunteers (28 females and 15 males) ingested 30 g/day of the yellow passion fruit peel flour for two months. The levels of blood glucose and fasting insulin, HOMA index and glycated hemoglobin were measured for each patient before and after dietary supplementation.
There was a significant difference in the fasting blood glucose values (P = 0.000) and glycated hemoglobin (P = 0.032) after supplementation. It was also seen a reduction in HOMA IR (P = 0.005) in the supplemented group, however it was not observed changes in insulin values for females. HOMA beta (P = 0.000) showed significant increase in its values for the studied group.
The supplementation used decreased insulin resistance in type 2 diabetic patients, suggesting a positive action in blood glucose control as adjuvant therapy in conventional treatments.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Identifying novel bio markers in gastro intestinal disease is a promising method where a comprehensive analysis of the metabolome is performed. Metabolomics has evolved enormously in the past decade, ...paving a path in gastro intestinal disease research, especially diseases which lead to high morbidity and mortality. Metabolomics involves identifying metabolites such as anti-oxidants, and amino acids etc., which are screened in the urine, feces and tissue samples. Certain cases employ advanced tools like GC-MS, 1HNMR and GC-MS/SPME which reveal valuable information concerning disease severity and differentiation. In light of escalating health care costs and risky invasive procedures, metabolomics can be chosen as a safe yet precise method for screening diseases like ulcerative colitis, Crohns' disease, celiac disease, and gastro intestinal cancers. The present review focuses on major advancements in gastro intestinal metabolomics, giving attention to which parameters are assessed, and to recent changes in metabolite analysis.
Giardiasis is a neglected disease, and there is a need for new molecules with less side effects and better activity against resistant strains. This work describes the evaluation of the giardicidal ...activity of thymol derivatives produced from the Morita–Baylis–Hillman reaction. Thymol acrylate was reacted with different aromatic aldehydes, using 1,4-diazabicyclo2.2.2octane (DABCO) as a catalyst. Eleven adducts (8 of them unpublished) with yields between 58 and 80% were obtained from this reaction, which were adequately characterized. The in silico prediction showed theoretical bioavailability after oral administration as well as antiparasitic activity against
Giardia lamblia.
Compound
4
showed better biological activity against
G. lamblia
. In addition to presenting antigiardial activity 24 times better than thymol, this MBHA was obtained in a short reaction time (3 h) with a yield (80%) superior to the other investigated molecules. The molecule was more active than the precursors (thymol and MBHA
12
) and did not show cytotoxicity against HEK-293 or HT-29 cells. In conclusion, this study presents a new class of drugs with better antigiardial activity in relation to thymol, acting as a basis for the synthesis of new bioactive molecules.
Graphic abstract
Molecular hybridization technique combined with the Morita–Baylis–Hillman reaction provided new thymol derivatives with giardicidal activity superior to the precursor molecules.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Børgesen is distributed worldwide in tropical and subtropical seas; belongs to the Dictyotaceae family, and has proven to be an exceptional source of biologically active compounds. Four compounds ...were isolated and identified, namely: dolastane diterpene new for the genus
; phaeophytin and hidroxy-phaeophytin new for the family Dictyotaceae, and; mannitol first described in this species. Saturated fatty acids as compared to the percentages of unsaturated fatty acids were shown to be present in greater abundance. Palmitic and linolenic acid were the main saturated and unsaturated acids, respectively. Cytotoxic and antioxidant activities were evaluated using human erythrocytes. In vivo evaluations of acute toxicity and genotoxicity were performed in mice. Methanolic extract of
presented antioxidant activity and did not induce cytotoxicity, genotoxicity or acute toxicity. Since
is already used as food, has essential fatty acids for the nutrition of mammals, does not present toxicity and has antioxidant activity, it can be considered as a potential nutraceutical.
Cissampelos sympodialis is a plant in northeastern Brazil used by the populace for treating respiratory diseases. Several studies have shown that ethanol leaf extracts have immunomodulatory and ...anti-inflammatory activities. Infusions are widely used, popular, and an ancient technique in traditional medicine, using hot water alone as the means of extraction. This study aimed to investigate acute toxicological potential of leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg to Rattus norvegicus, combined with an in silico study of 117 alkaloids present in the Cissampelos genus; five (5) of which were determined to have high toxicity (21, 8, 93, 32 and 88), and five (5) having both low toxicity (57, 77, 28, 25 and 67) and low liver metabolism. The in vivo toxicological evaluation showed that male water consumption decreased, and the feed intake decreased in both sexes. Yet, the figures as to change in weight gain of the animals were not statistically sufficient. As for the biochemical parameters, there was an increase in urea, and decreases in uric acid and AST in males. In females, there was a decrease in albumin and globulin which consequently leads to a total protein decrease. Despite biochemical changes suggestive of kidney damage, the histological sections revealed no kidney or liver changes. The results therefore indicate that despite presenting alkaloids which may be toxic, the genus Cissampelos, or leaf infusions of Cissampelos sympodialis, when applied orally at a dose of 2000mg/kg present low toxicity.
: The mechanisms underlying the cardiovascular responses evoked by milonine (i.v.), an alkaloid, were investigated in rats. In normotensive rats, milonine injections produced hypotension and ...tachycardia, which were attenuated after Nw‐nitro‐l‐arginine methyl esther (l‐NAME; 20 mg/kg, i.v.). In phenylephrine (10 μM), pre‐contracted mesenteric artery rings, milonine (10−10 M to 3 × 10−4 M) caused a concentration‐dependent relaxation (EC50 = 1.1 × 10−6 M, Emax = 100 ± 0.0%) and this effect was rightward shifted after either removal of the vascular endothelium (EC50 = 1.6 × 10−5, p < 0.001), or after l‐NAME 100 μM (EC50 = 6.2 × 10−5, p < 0.001), hydroxocobalamin 30 μM (EC50 = 1.1 × 10−4, p < 0.001) or ODQ 10 μM (EC50 = 1.9 × 10−4p < 0.001). In addition, in rabbit aortic endothelial cells, milonine increased NO3− levels. The relaxant effect induced by milonine was attenuated in the presence of KCl (20 mM), a modulator efflux K+ (EC50 = 1.2 × 10−5, p < 0.001), or different potassium channel blockers such as glibenclamide (10 μM) (EC50 = 6.3 × 10−5, p < 0.001), TEA (1 mM) (EC50 = 2.3 × 10−5 M, n = 6) or Charybdotoxin (0.2 μM) plus apamin (0.2 μM) (EC50 = 3.9 × 10−4 M, n = 7). In addition, pre‐contraction with high extracellular potassium concentration prevented milonine‐induced vasorelaxation (EC50 = 1.0 × 10−4, p < 0.001). Milonine also reduced CaCl2‐induced contraction in Ca2+‐free solution containing KCl (60 mM). In conclusion, using combined functional and biochemical approaches, we demonstrated that the hypotensive and vasorelaxant effects produced by milonine are, at least in part, mediated by the endothelium, likely via nitric oxide release, activation of nitric oxide‐cGMP pathway and opening of K+ channels.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The purpose of the study was to evaluate the efficacy of an extract of Panax ginseng in patients with fibromyalgia. A randomized, double-blind, controlled clinical trial was carried out over 12 weeks ...to compare the effects of P. ginseng (100mg/d) with amitriptyline (25mg/d) and placebo in 38 patients with fibromyalgia: 13 in Group I (amitriptyline), 13 in Group II (placebo), and 12 in Group III (P. ginseng). Ratings on the Visual Analogue Scale (VAS) revealed a reduction in pain in the P. ginseng group (p < .0001), an improvement in fatigue (p < .0001) and an improvement in sleep (p < .001), with respect to baseline characteristics, but there were no differences between the three groups. With respect to anxiety, improvements occurred in the P. ginseng group compared to baseline (p < .0001); however, amitriptyline treatment resulted in significantly greater improvements (p < .05).
P. ginseng reduced the number of tender points and improved patients’ quality of life (using the Fibromyalgia Impact Questionnaire - FIQ); however, there were no differences between groups.
The beneficial effects experienced by patients for all parameters suggest a need for further studies to be performed on the tolerability and efficacy of this phytotherapic as a complementary therapy for fibromyalgia.
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GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The chemical composition, antitumor activity and toxicity of the essential oil from
leaves (OEL) were investigated. The major constituents were thymol (46.5%), carvacrol (31.7%),
-cymene (9%), and ...γ-terpinene (2.9%). To evaluate the toxicity of OEL in non-tumor cells, the hemolytic assay with Swiss mice erythrocytes was performed. The concentration producing 50% hemolysis (HC
) was 300 μg/mL. Sarcoma 180 tumor growth was inhibited in vivo 38% at 50 mg/kg, and 60% at 100 mg/kg, whereas 5-FU at 50 mg/kg caused 86% inhibition. OEL displays moderate gastrointestinal and hematological toxicity along with causing some alteration in liver function and morphology. However, the changes were considered reversible and negligible in comparison to the effects of several anticancer drugs. In summary, OEL displays in vivo antitumor activity and a moderate toxicity, which suggests further pharmacological study.
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