Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives

2020 ◽  
Vol 18 (1) ◽  
pp. 41-51 ◽  
Author(s):  
Mahdieh Safakish ◽  
Zahra Hajimahdi ◽  
Mohammad R. Aghasadeghi ◽  
Rouhollah Vahabpour ◽  
Afshin Zarghi
Keyword(s):  
Therapeutic Index ◽  
In Vivo Studies ◽  
One Pot ◽  
Design Synthesis ◽  
Phenyl Derivative ◽  
Hiv Therapy ◽  
Anti Hiv Agents ◽  
Anti Hiv

Background: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. Objective: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. Method: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-compo Results: In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well. Conclusion: Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

Antitumor activity of esorubicin in human tumor clonogenic assay with comparisons to doxorubicin.

1984 ◽  
Vol 2 (4) ◽  
pp. 282-286 ◽  
Author(s):  
S E Salmon ◽  
L Young ◽  
B Soehnlen ◽  
R Liu
Keyword(s):  
Antitumor Activity ◽  
Clonogenic Assay ◽  
Human Tumor ◽  
Therapeutic Index ◽  
In Vivo Studies ◽  
Early Results ◽  
Colony Forming Units ◽  
Human Solid Tumors

The new anthracycline analog, esorubicin (4'deoxy-doxorubicin, ESO), was tested against fresh biopsies of human solid tumors in vitro in clonogenic assay and the results were contrasted to those obtained with doxorubicin (DOX). ESO appeared to be significantly more potent on a weight basis than DOX in these studies, and exhibited a spectrum of antitumor activity in vitro that was in general qualitatively similar to that observed with DOX. In vitro antitumor activity was observed in a wide variety of human cancers including anthracycline-sensitive tumor types. ESO has previously been reported to have decreased cardiac toxicity in preclinical models as compared to DOX. Comparative testing of these anthracyclines on granulocyte-macrophage colony-forming units (GM-CFUs) and tumor colony forming units (TCFUs) indicated that the in vitro GM-CFU assay is more sensitive to these myelosuppressive drugs than are TCFUs, and underscores the need for in vivo studies to determine normal tissue toxicity and the therapeutic index of a drug. Early results of phase I studies suggest that with respect to myelosuppression, the maximally tolerated dose of ESO will be about half that of DOX. The increased in vitro antitumor potency observed for ESO and a spectrum of activity (even at one half the dose of DOX) supports the broad testing of ESO in the clinic to determine whether it will prove to be a more effective and less toxic anthracycline.

scholarly journals Ingenol Derivatives are Highly Potent and Selective Inhibitors of HIV Replication in Vitro

1996 ◽  
Vol 7 (5) ◽  
pp. 230-236 ◽  
Author(s):  
M. Fujiwara ◽  
K. Ijichi ◽  
K. Tokuhisa ◽  
K. Katsuura ◽  
G.-Y.-S. Wang ◽  
...  
Keyword(s):  
Syncytium Formation ◽  
Selective Inhibitor ◽  
Host Cells ◽  
Hiv Replication ◽  
Virus Adsorption ◽  
Mechanism Of Inhibition ◽  
Anti Hiv Agents ◽  
Anti Hiv

Ingenol 3,5,20-triacetate has recently been identified as a highly potent and selective inhibitor of HIV replication in vitro. To evaluate the potential of ingenol derivatives as anti-HIV agents, several ingenol derivatives have been synthesized and investigated for their anti-HIV activities, structure-activity relationships, and possible mechanisms of action. Among the ingenol derivatives, 13-hydroxyingenol-3-(2,3-dimethylbutanoate)-13-dodecanoate (RD4-2138) proved to be a highly potent and selective inhibitor of HIV replication. Its 50% effective concentration for viral replication in MT-4 cells was 0.07-0.5 nM depending on viral strains, including HIV-2. This concentration was approximately 105-fold lower than its cytotoxic threshold. RD4-2138 was also inhibitory to the syncytium formation induced by cocultivation of Molt-4 cells with Molt-4/IIIB cells (Molt-4 cells chronically infected with HIV-1). Some correlation was observed with the ingenol derivatives between their inhibitory effects on HTLV-IIIB replication and surface CD4 expression in MT-4 cells, suggesting that the mechanism of inhibition is in part attributed to the inhibition of virus adsorption through down-regulation of CD4 molecules in the host cells. However, such correlation was not identified between the inhibition of HTLV-IIIB and the activation of protein kinase C. Thus, they might have a potential as effective anti-HIV agents when toxicity in vivo could be elucidated.

Traditional Medicines, HIV, and Related Infections

2011 ◽  
Vol 23 (1) ◽  
pp. 159-164 ◽  
Author(s):  
M. Patel ◽  
P. Bessong ◽  
H. Liu
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Ethical Issues ◽  
Mechanisms Of Action ◽  
Antiretroviral Drugs ◽  
In Vivo Studies ◽  
Traditional Medicines ◽  
Anti Hiv

Traditional medicines are an integral part of health care worldwide, even though their efficacy has not been scientifically proven. HIV-infected individuals may use them singularly or in combination with conventional medicines. Many in vitro studies have proven the anti-HIV, anti- Candida, and anti–herpes simplex virus potential of traditional plants and identified some of the mechanisms of action. Very few in vivo studies are available that involve a small number of participants and show controversial results. In addition, knowledge is limited of the role of traditional medicines in the enhancement of the immune system. The use of traditional medicines with antiretroviral drugs (ARVs) has created a problem because drug interactions compromise the efficacy of ARVs. Several currently popular plants have been studied in the laboratory for their interaction with ARVs, with disadvantageous results. Unfortunately, no clinical trials are available. The science of traditional medicines is relatively new and is at present being modernized worldwide. However, there are still ethical issues regarding traditional medicines that need to be addressed—for example, regulations regarding quality control and standardization of medicines, regulation and education of healers who deliver these medicines, and unregulated clinical trials. The workshop addressed the following questions about traditional medicine and their use in HIV infection: What are the mechanisms of action of anti-HIV traditional medicines? Should traditional medicines be used in conjunction with ARV? Do traditional medicines enhance the immune system? Should medicinal plants be used for the control of oral infections associated with HIV? What are the ethical issues surrounding the use of traditional medicines for the treatment of HIV and associated infections?

scholarly journals Design, Synthesis, and Validation of a Novel [11C]Promethazine PET Probe for Imaging Abeta Using Autoradiography

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2182
Author(s):  
Clayton A. Whitmore ◽  
Mariam I. Boules ◽  
William J. Behof ◽  
Justin R. Haynes ◽  
Dmitry Koktysh ◽  
...  
Keyword(s):  
Radiochemical Purity ◽  
In Vivo Studies ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Molar Activity ◽  
Rp Hplc ◽  
Model Of Alzheimer’S Disease ◽  
Antihistamine Drug

Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer’s disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this work, we report the design and synthesis of a novel [11C]promethazine PET radioligand for future in vivo studies. The [11C]promethazine was isolated by RP-HPLC with radiochemical purity >95% and molar activity of 48 TBq/mmol. The specificity of the probe was demonstrated using human hippocampal tissues via autoradiography.

Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies

2005 ◽  
Vol 55 (6) ◽  
pp. 565-576 ◽  
Author(s):  
Debora G. Rodrigues ◽  
Durvanei A. Maria ◽  
Denise C. Fernandes ◽  
Claudete J. Valduga ◽  
Ricardo D. Couto ◽  
...  
Keyword(s):  
Therapeutic Index ◽  
In Vivo Studies

scholarly journals Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells

Biomedicines ◽  
2020 ◽  
Vol 8 (5) ◽  
pp. 103 ◽  
Author(s):  
Vaishali Aggarwal ◽  
Hardeep Singh Tuli ◽  
Jagjit Kaur ◽  
Diwakar Aggarwal ◽  
Gaurav Parashar ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Clinical Stage ◽  
Therapeutic Index ◽  
In Vivo Studies ◽  
Regulation Of Transcription ◽  
Cellular Processes ◽  
Garcinia Indica ◽  
Anti Cancer

Garcinol, a polyisoprenylated benzophenone, is the medicinal component obtained from fruits and leaves of Garcinia indica (G. indica) and has traditionally been extensively used for its antioxidant and anti-inflammatory properties. In addition, it has been also been experimentally illustrated to elicit anti-cancer properties. Several in vitro and in vivo studies have illustrated the potential therapeutic efficiency of garcinol in management of different malignancies. It mainly acts as an inhibitor of cellular processes via regulation of transcription factors NF-κB and JAK/STAT3 in tumor cells and have been demonstrated to effectively inhibit growth of malignant cell population. Numerous studies have highlighted the anti-neoplastic potential of garcinol in different oncological transformations including colon cancer, breast cancer, prostate cancer, head and neck cancer, hepatocellular carcinoma, etc. However, use of garcinol is still in its pre-clinical stage and this is mainly attributed to the limitations of conclusive evaluation of pharmacological parameters. This necessitates evaluation of garcinol pharmacokinetics to precisely identify an appropriate dose and route of administration, tolerability, and potency under physiological conditions along with characterization of a therapeutic index. Hence, the research is presently ongoing in the dimension of exploring the precise metabolic mechanism of garcinol. Despite various lacunae, garcinol has presented with promising anti-cancer effects. Hence, this review is motivated by the constantly emerging and promising positive anti-cancerous effects of garcinol. This review is the first effort to summarize the mechanism of action of garcinol in modulation of anti-cancer effect via regulation of different cellular processes.

scholarly journals High Therapeutic Index of Factor C Sushi Peptides: Potent Antimicrobials against Pseudomonas aeruginosa

2001 ◽  
Vol 45 (10) ◽  
pp. 2820-2825 ◽  
Author(s):  
Yin Hoe Yau ◽  
Bow Ho ◽  
Nguan Soon Tan ◽  
Miang Lon Ng ◽  
Jeak Ling Ding
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Therapeutic Potential ◽  
Therapeutic Index ◽  
In Vivo Studies ◽  
C Protein ◽  
High Therapeutic Index ◽  
Viable Bacteria ◽  
Factor C

ABSTRACT Factor C protein isolated from the horseshoe crab,Carcinoscorpius rotundicauda, has endotoxin binding capability. Synthetic peptides of 34 amino acids based on the sequence of two regions of factor C (Sushi 1 and Sushi 3) as well as their corresponding mutants exhibited activities against 30 clinical isolates of Pseudomonas aeruginosa. Collectively, all four peptides demonstrated exceptionally effective bactericidal activity againstP. aeruginosa with 90% minimal bactericidal concentrations (MBC90s) in the range of 0.06 to 0.25 μg/ml (16 to 63 nM). Viable bacteria were reduced by 90% after 7 min and were totally eradicated within 40 to 50 min. These peptides are minimally hemolytic against both rabbit and human erythrocytes even at concentrations up to 1,600-fold their MBC90s. Both in vitro and in vivo studies indicate that cytotoxic effects are small even at 1,000-fold their MBC90s. Furthermore, the Sushi peptides are tolerant of high-salt and adverse pH conditions. These findings demonstrate the promising therapeutic potential of the Sushi peptides.

scholarly journals Design, synthesis and cytotoxic evaluation of 2-amino-4- aryl-6-substituted pyridine-3,5-dicarbonitrile derivatives

2021 ◽  
Vol 20 (10) ◽  
pp. 2127-2133
Author(s):  
Amr S. Abu Lila ◽  
Marwa H. Abdallah ◽  
El-Sayed Khafagy ◽  
Tamer M. Shehata ◽  
Mahmoud S. Soliman ◽  
...  
Keyword(s):  
Cell Lines ◽  
Condensation Reaction ◽  
In Vitro Cytotoxicity ◽  
In Vivo Studies ◽  
Primary Amines ◽  
Binding Modes ◽  
One Pot ◽  
Multicomponent Condensation

Purpose: To synthesize novel pyridine derivatives and evaluate their efficiency as potent inhibitors of cyclin dependent kinase 2 (CDK2) enzyme for cancer therapy.Methods: Pyridine scaffold were synthesized using one-pot multicomponent condensation reaction of arylidine with different primary amines. The cytotoxic potential of the new compounds was assessed using various cell lines. Furthermore, molecular docking studies based on the crystal structure of CDK2 was carried out to determine the possible binding modes that influence the anticancer activities.Results: The results indicate that one-pot multicomponent reaction generated a series of functionalized pyridines with good yield. In vitro cytotoxicity study revealed superior cytotoxicity of the designed compounds against prostate and cervical cancer cell lines compared to 5-fluorouracil (standard anticancer compound) with half-maximal inhibitory concentration (IC50) values of 0.1 – 0.85 and 1.2 –74.1 μM, respectively. Finally, molecular modeling simulation of the newly synthesized compounds showed that they fit well and are stabilized into CDK2 active site via hydrogen bonding and hydrophobic interactions.Conclusion: The results indicate that the newly synthesized pyridine can exert potent anticancer activity presumably via inhibition of CDK2. However, this will need to be confirmed in in vivo studies.

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