ABSTRACT
We investigated the role of triterpene barbinervic acid from Eugenia punicifolia dichloromethane extract in vasopressor responses. Renal arteries were cannulated and perfused with Krebs-Hepes solution. Changes in aorta isometric tension were recorded and transferred to a data acquisition system. Cumulative curves were constructed based on the maximum effect of agonists. Barbinervic acid reduced the renal tonus induced by NA in a NO-dependent manner (IC50 = 30 µM). Triterpene (70 µM) also induced rapid and transient relaxation in aorta that had been precontracted with K+ (53.2 ± 0.05%) or phenylephrine (36.7 ± 0.05%). In silico data revealed two possible active sites for interactions between barbinervic acid and NO synthase. Barbinervic acid showed a vasodilator effect and could potentially be used as a template for developing new molecules for the treatment of cardiovascular disease.
Subject(s)
Eugenia , Triterpenes , Computer Simulation , Plant Extracts/pharmacology , Plant Leaves , Triterpenes/pharmacologyABSTRACT
Herpes simplex virus infections have been described in the medical literature for centuries, yet the the drugs available nowadays for therapy are largely ineffective and low oral bioavailability plays an important role on the inefficacy of the treatments. Additionally, the details of the inhibition of Herpes Virus type 1 are still not fully understood. Studies have shown that several viruses encode one or more proteases required for the production new infectious virions. This study presents an analysis of the interactions between HSV-1 protease and benzoxazinone derivatives through a combination of structure-activity relationships, comparative modeling and molecular docking studies. The structure activity relationship results showed an important contribution of hydrophobic and polarizable groups and limitations for bulky groups in specific positions. Two Herpes Virus type 1 protease models were constructed and compared to achieve the best model which was obtained by MODELLER. Molecular docking results pointed to an important interaction between the most potent benzoxazinone derivative and Ser129, consistent with previous mechanistic data. Moreover, we also observed hydrophobic interactions that may play an important role in the stabilization of inhibitors in the active site. Finally, we performed druglikeness and drugscore studies of the most potent derivatives and the drugs currently used against Herpes virus.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzoxazines/chemistry , Benzoxazines/pharmacology , Herpesvirus 1, Human/drug effects , Herpesvirus 1, Human/enzymology , Models, Molecular , Peptide Hydrolases/chemistry , Binding Sites , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Conformation , Molecular Docking Simulation , Molecular Weight , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protein Binding , Structure-Activity RelationshipABSTRACT
Benzothiazole hydrazones have been synthesized and evaluated for their in vitro antiproliferative activity against three human cancer cell lines: HL-60 (leukemia), MDAMB-435 (breast) and HCT-8 (colon). The good cytotoxicity for the three cancer cell lines and theoretical profile of compounds 3o and 3p pointed them as promising lead molecules for anticancer drug design.
Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Hydrazines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Hydrazines/chemical synthesis , Hydrazines/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (E(LUMO)-E(HOMO)), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Binding Sites , HIV-1/drug effects , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Molecular Docking Simulation/methods , Structure-Activity RelationshipABSTRACT
In this paper, we describe the antinociceptive activity, molecular modeling and in silico ADMET screening of a series of sulphonyl-hydrazone and sulphonamide imidobenzene derivatives. Among these compounds, the sulphonyl-hydrazones 9 and 11 showed the most potent analgesic activity (ID(50) = 5.1 and 6.8 µmol/kg, respectively). Interestingly, all derivatives evaluated in this study have a better analgesic profile than the control drugs, acetyl salicylic acid and acetaminophen. Derivative 9 was the most promising compound; with a level of activity that was 24 times higher than the control drugs. Our SAR study showed a relationship among the distribution of the frontier orbital HOMO coefficients, HOMO-LUMO energy gap of these molecules and their reactivity. The best analgesic compounds (including 6, 9, 10, 11 and 12) fulfilled the Lipinski "rule-of-five", which is theoretically important for good drug absorption and permeation.
Subject(s)
Analgesics/pharmacology , Drug Design , Hydrazones/pharmacology , Imides/pharmacology , Sulfonamides/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Disease Models, Animal , Hydrazones/chemical synthesis , Hydrazones/chemistry , Hydrazones/therapeutic use , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Imides/chemical synthesis , Imides/chemistry , Imides/therapeutic use , Mice , Models, Molecular , Molecular Structure , Pain/drug therapy , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/therapeutic useABSTRACT
Current drugs for treating leishmaniasis are still associated with significant toxicity and failure rates. Thus, new effective and less toxic antileishmanial agents are still in need. Herein, we tested a series of sulfonamide 4-methoxychalcone derivatives against L. amazonensis promastigote and amastigote forms to identify its antileishmanial profile against this species compared to L. braziliensis. In addition, we used molecular modeling tools to determine stereoelectronic features that may lead to the antileishmanial profile. Interestingly, all tested compounds were able to affect L. amazonensis promastigote form in a concentration-dependent manner and with low cytotoxicity, except for derivative 3g. However, our results showed that compound 3f (para-Cl) presents the best profile against both L. amazonensis forms (promastigote and amastigote), differently from that observed for L. braziliensis, when compound 3i was the most active. Structure-activity relationship (SAR) analysis of these derivatives pointed molecular volume, HOMO density, and conformational aspects as important characteristics for parasitic profile. Overall, sulfonamide 4-methoxychalcone derivatives may be pointed out not only as lead compounds for treating leishmaniasis (i.e., 3f) but also as experimental tools presenting parasite-selectivity (i.e., 3i).
