Design strategies, chemistry and therapeutic insights of multi-target directed ligands as antidepressant agents

2021 ◽  
Vol 19 ◽  
Author(s):  
Karanvir Singh ◽  
Rohit Bhatia ◽  
Bhupinder Kumar ◽  
Gurpreet Singh ◽  
Vikramdeep Monga
Keyword(s):  
Therapeutic Efficacy ◽  
Therapeutic Potential ◽  
Antidepressant Drugs ◽  
Biological Evaluation ◽  
World Health ◽  
Design Strategies ◽  
Antidepressant Agents ◽  
Single Target ◽  
In Silico Studies ◽  
Health Organization

: Depression is one of the major disorders of the central nervous system worldwide and causes disability and functional impairment. According to the World Health Organization, around 265 million people worldwide are affected by depression. Currently marketed antidepressant drugs take weeks or even months to show anticipated clinical efficacy but remain ineffective in treating suicidal thoughts and cognitive impairment. Due to its multifactorial complexity, single-target drugs did not always produce satisfactory results and lacks the desired level of therapeutic efficacy. Recent literature reports revealed improved therapeutic potential of multi-target directed ligands due to their synergistic potency and better safety. Medicinal chemists have gone to great extents for the design of multi-target ligands by generating structural hybrids of different key pharmacophores with improved binding affinities and potency towards different receptors or enzymes. This article compiled the design strategies of recently published multi-target directed ligands as antidepressant agents. Their biological evaluation, structural-activity relationships, mechanistic and in silico studies were also described. This article will be highly useful for the researchers to design and develop multi-target ligands as antidepressants with high potency and therapeutic efficacy.

New Efavirenz Derivatives and 1,2,3-Triazolyl-phosphonates as Inhibitors of Reverse Transcriptase of HIV-1

2018 ◽  
Vol 18 (17) ◽  
pp. 1494-1505 ◽  
Author(s):  
Carolina C.P. Costa ◽  
Nubia Boechat ◽  
Monica M. Bastos ◽  
Fernando de C. da Silva ◽  
Andressa Marttorelli ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Triazole Ring ◽  
Biological Evaluation ◽  
World Health ◽  
Hiv Reverse Transcriptase ◽  
Ic50 Values ◽  
Health Organization ◽  
Hiv Drugs ◽  
Immunodeficiency Syndrome ◽  
New Compounds

Background: According to the World Health Organization (WHO), the fight against Acquired Immunodeficiency Syndrome (AIDS) is still one of the most significant challenges facing humanity. Worldwide, it is estimated that 36.7 million people are infected by the Human Immunodeficiency Virus (HIV). Despite the variety of available drugs, the search for new enzymatic inhibitors of HIV is still important due to the presence of adverse effects and the development of resistant strains. Therefore, the present study aimed to design, synthesize, and biologically evaluate novel inhibitors of HIV Reverse Transcriptase (RT). Materials and Methods: These compounds were obtained in two series, and compounds in both series contain a 1,2,3-triazole ring in their structures. The compounds in the first series are Efavirenz (EFV) analogues with the N-1 position substituted by another important fragment as described in the medicinal chemistry literature on anti-HIV drugs. The second series has a phosphonate chain similar to that in the structure of Tenofovir Disoproxil Fumarate (TDF). Results and Conclusion: The results of the biological evaluation showed that all compounds presented high RT inhibition values and lower or comparable inhibitory concentrations (the concentration needed to reduce the enzymatic activity by 50%, IC50 values, 0.8-1.9 µM). Among the compounds in the first series, the three with the lowest IC50 values had values between 0.8-0.9 µM, and of those in the second series, the most potent had an IC50 value of 1.1 µM; compounds in both series were equipotent to TDF (1.2 µM). Thus, the new compounds could be considered lead compounds for the development of new antiretroviral compounds.

scholarly journals COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection

2021 ◽  
Vol 14 (1) ◽  
pp. 71
Author(s):  
Katarzyna Kotfis ◽  
Kacper Lechowicz ◽  
Sylwester Drożdżal ◽  
Paulina Niedźwiedzka-Rystwej ◽  
Tomasz K. Wojdacz ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Therapeutic Potential ◽  
Severe Pneumonia ◽  
Therapeutic Benefit ◽  
World Health ◽  
Therapeutic Effects ◽  
Severe Acute Respiratory Infection ◽  
Dual Action ◽  
Health Organization ◽  
Transmembrane Serine Protease

In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential.

scholarly journals Design and reporting considerations for genetic screening tests

2019 ◽  
Author(s):  
Jill Hagenkord ◽  
Birgit Funke ◽  
Emily Qian ◽  
Madhuri Hegde ◽  
Kevin B Jacobs ◽  
...  
Keyword(s):  
Genetic Screening ◽  
World Health ◽  
Screening Tests ◽  
Clinical Indication ◽  
Test Design ◽  
Design Strategies ◽  
Predictive Values ◽  
Inherited Diseases ◽  
Health Communities ◽  
Health Organization

Testing asymptomatic individuals for unsuspected conditions is not new to the medical and public health communities and protocols to develop screening tests are well-established. However, the application of screening principles to inherited diseases presents unique challenges. Unlike most screening tests, the natural history and disease prevalence of most rare inherited diseases in an unselected population are unknown. It is difficult or impossible to obtain a “truth set” cohort for clinical validation studies. As a result, it is not possible to accurately calculate clinical positive and negative predictive values for “likely pathogenic” genetic variants, which are commonly returned in genetic screening assays. In addition, many of the genetic conditions included in screening panels do not have clinical confirmatory tests. All of these elements are typically required to justify the development of a screening test, according to the World Health Organization screening principles. Nevertheless, as the cost of DNA sequencing continues to fall, more individuals are opting to undergo genomic testing in the absence of a clinical indication. Despite the challenges, reasonable estimates can be deduced and used to inform test design strategies. Here, we review test design principles and apply them to genetic screening.

scholarly journals Design and reporting considerations for genetic screening tests

2019 ◽  
Author(s):  
Jill Hagenkord ◽  
Birgit Funke ◽  
Emily Qian ◽  
Madhuri Hegde ◽  
Kevin B Jacobs ◽  
...  
Keyword(s):  
Genetic Screening ◽  
World Health ◽  
Screening Tests ◽  
Clinical Indication ◽  
Test Design ◽  
Design Strategies ◽  
Predictive Values ◽  
Inherited Diseases ◽  
Health Communities ◽  
Health Organization

Testing asymptomatic individuals for unsuspected conditions is not new to the medical and public health communities and protocols to develop screening tests are well-established. However, the application of screening principles to inherited diseases presents unique challenges. Unlike most screening tests, the natural history and disease prevalence of most rare inherited diseases in an unselected population are unknown. It is difficult or impossible to obtain a “truth set” cohort for clinical validation studies. As a result, it is not possible to accurately calculate clinical positive and negative predictive values for “likely pathogenic” genetic variants, which are commonly returned in genetic screening assays. In addition, many of the genetic conditions included in screening panels do not have clinical confirmatory tests. All of these elements are typically required to justify the development of a screening test, according to the World Health Organization screening principles. Nevertheless, as the cost of DNA sequencing continues to fall, more individuals are opting to undergo genomic testing in the absence of a clinical indication. Despite the challenges, reasonable estimates can be deduced and used to inform test design strategies. Here, we review test design principles and apply them to genetic screening.

Antidepressants

2012 ◽  
pp. 1185-1198
Author(s):  
Zubin Bhagwagar ◽  
George R. Heninger
Keyword(s):  
Burden Of Disease ◽  
Antidepressant Drugs ◽  
Public Health Problem ◽  
Premature Mortality ◽  
Primary Treatment ◽  
World Health ◽  
Years Of Life Lost ◽  
Major Public Health Problem ◽  
Treatment Of Depression ◽  
Health Organization

Major depressive disorder is a serious, recurrent illness which levies a crippling toll on individuals, families, and society in general. The importance of depression as a major public health problem is emphasized by findings from the World Health Organization Global Burden of Disease survey in showing that in 1990 it was the fourth largest cause of burden of disease (i.e. years of life lost due either to premature mortality or to years lived with a disability). It has been estimated that by the year 2020 it is expected to be the second largest cause of burden of disease. Depression is underdiagnosed and frequently under-treated, and depressed individuals have a much higher risk for suicide. The primary treatment for depression involves the use of antidepressant drugs, and it is therefore important that clinicians become familiar with and adept in utilizing this important group of compounds. Although primarily used for the treatment of depression, drugs within this category also have a number of other important uses. A thorough understanding of the pharmacology of antidepressants will aid the clinician in the selective use of these drugs for patients with depression as well as patients with a number of other disorders.

scholarly journals Continued low efficacy of artemether-lumefantrine in Angola, 2019

2020 ◽  
Author(s):  
Pedro Rafael Dimbu ◽  
Roberta Horth ◽  
Ana Luisa M. Cândido ◽  
Carolina Miguel Ferreira ◽  
Felismina Caquece ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Confidence Interval ◽  
Microsatellite Markers ◽  
Therapeutic Efficacy ◽  
World Health ◽  
The Third ◽  
Kaplan Meier ◽  
Late Failure ◽  
Health Organization ◽  
Parasitological Response

Background: Biennial therapeutic efficacy monitoring is a crucial activity for ensuring efficacy of currently used artemisinin-based combination therapy in Angola. Methods: Children with acute uncomplicated P. falciparum infection in sentinel sites in Benguela, Zaire, and Lunda Sul Provinces were treated with artemether-lumefantrine (AL) or artesunate amodiaquine (ASAQ) and followed for 28 days to assess clinical and parasitological response. Molecular correction was performed using seven microsatellite markers. Samples from treatment failures were genotyped for the pfk13, pfcrt, and pfmdr1 genes. Results: Day 3 clearance rates were ≥95% in all arms. Uncorrected Day-28 Kaplan-Meier efficacy estimates ranged from 84.2 to 90.1% for the AL arms, and 84.7 to 100% for the ASAQ arms. Corrected Day-28 estimates were 87.6% (95% Confidence interval [CI]: 81–95%) for the AL arm in Lunda Sul, 92.2% (95%CI: 87-98%) for AL in Zaire, 95.6% (95%CI: 91-100%) for ASAQ in Zaire, 98.4% (95%CI: 96-100%) for AL in Benguela, and 100% for ASAQ in Benguela and Lunda Sul. All 103 analyzed samples had wildtype pfk13 sequences. The 76T pfcrt allele was found in most (92%, 11/12) ASAQ late failure samples but only 16% (4/25) of AL failure samples. The N86 pfmdr1 allele was found in 97% (34/35) of treatment failures. Conclusion: AL efficacy in Lunda Sul was below the 90% World Health Organization threshold, the third time in four rounds that this threshold was crossed for an AL arm in Angola. In contrast, observed ASAQ efficacy has not been below 95% to date in Angola, including this latest round.

scholarly journals Design and reporting considerations for genetic screening tests

2019 ◽  
Author(s):  
Jill Hagenkord ◽  
Birgit Funke ◽  
Emily Qian ◽  
Madhuri Hegde ◽  
Kevin B Jacobs ◽  
...  
Keyword(s):  
Genetic Screening ◽  
World Health ◽  
Screening Tests ◽  
Clinical Indication ◽  
Test Design ◽  
Design Strategies ◽  
Predictive Values ◽  
Inherited Diseases ◽  
Health Communities ◽  
Health Organization

Testing asymptomatic individuals for unsuspected conditions is not new to the medical and public health communities and protocols to develop screening tests are well-established. However, the application of screening principles to inherited diseases presents unique challenges. Unlike most screening tests, the natural history and disease prevalence of most rare inherited diseases in an unselected population are unknown. It is difficult or impossible to obtain a “truth set” cohort for clinical validation studies. As a result, it is not possible to accurately calculate clinical positive and negative predictive values for “likely pathogenic” genetic variants, which are commonly returned in genetic screening assays. In addition, many of the genetic conditions included in screening panels do not have clinical confirmatory tests. All of these elements are typically required to justify the development of a screening test, according to the World Health Organization screening principles. Nevertheless, as the cost of DNA sequencing continues to fall, more individuals are opting to undergo genomic testing in the absence of a clinical indication. Despite the challenges, reasonable estimates can be deduced and used to inform test design strategies. Here, we review test design principles and apply them to genetic screening.

scholarly journals Photodynamic Therapy (PDT): An Alternative Approach for Combating COVID-19

2021 ◽  
Vol 11 (5) ◽  
pp. 12808-12830
Keyword(s):  
Photodynamic Therapy ◽  
Alternative Treatment ◽  
Therapeutic Potential ◽  
World Health ◽  
Treatment Modalities ◽  
Target Cells ◽  
Safety Issues ◽  
Alternative Approach ◽  
Psoralen Derivatives ◽  
Health Organization

The COVID-19 disease initially originated in Wuhan (China) and then spread worldwide has been declared a pandemic by the World Health Organization (WHO). Many attempts are ongoing to find an effective therapeutic treatment and vaccine to cure or prevent the disease, but the success is very little. Even some of the approved vaccines are also disputed for safety issues. This is the time where we should think of alternative treatments to control the disease effectively. Photodynamic therapy (PDT) is a technique that is widely used in cancer treatment and against various microbes. In this technique, a light-induced photosensitizer generates reactive oxygen species (ROS), ultimately killing the target cells. Considering these facts, an attempt has been made to review the current literature on viral inactivation using PDT approach. Accordingly, the mechanism of PDT action has been discussed, along with an update on the use of various photosensitizers (PSs) and nanoparticles. The capsid proteins and nucleic acid (RNA) of SARS-CoV-2 can be a possible target for PDT. To understand this interaction further, computational modeling studies have been discussed to help design effective PSs. Overall, the PDT technique has therapeutic potential and should be tested as a complementary or alternative treatment for control of COVID-19 using the PSs like curcumin, psoralen derivatives, riboflavin, etc. This review discusses COVID-19, its outbreak, diagnosis, the existing treatment modalities, and how PDT can be an effective alternative treatment for controlling the disease.

scholarly journals Emergence of Plasmodium vivax Resistance to Chloroquine in French Guiana

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Lise Musset ◽  
Christophe Heugas ◽  
Richard Naldjinan ◽  
Denis Blanchet ◽  
Pascal Houze ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Therapeutic Efficacy ◽  
French Guiana ◽  
Gene Copy Number ◽  
Chloroquine Resistance ◽  
World Health ◽  
Gene Copy ◽  
Content Type ◽  
Gene Copy Number Variation ◽  
Health Organization

ABSTRACT In South America, Plasmodium vivax resistance to chloroquine was recently reported in Brazil and Bolivia. The objective of this study was to collect data on chloroquine resistance in French Guiana by associating a retrospective evaluation of therapeutic efficacy with an analysis of recurrent parasitemia from any patients. Patients with P. vivax infection, confirmed by microscopy and a body temperature of ≥37.5°C, were retrospectively identified at Cayenne Hospital between 2009 and 2015. Follow-up and treatment responses were performed according to the World Health Organization protocol. Parasite resistance was confirmed after dosage of a plasma concentration of chloroquine and microsatellite characterization. The pvmdr1 and pvcrt-o genes were analyzed for sequence and gene copy number variation. Among the 172 patients followed for 28 days, 164 presented adequate clinical and parasitological responses. Eight cases of treatment failures were identified (4.7%; n = 8/172), all after 14 days. The therapeutic efficacy of chloroquine was estimated at 95.3% (95% confidence interval [CI], 92.5 to 98.1%; n = 164/172). Among the eight failures, five were characterized: two cases were true P. vivax chloroquine resistance (1.2%; 95% CI, 0 to 2.6%; n = 2/172), and three cases were found with subtherapeutic concentrations of chloroquine. No particular polymorphism in the Plasmodium vivax pvmdr1 and pvcrt-o genes was identified in the resistant parasites. This identified level of resistance of P. vivax to chloroquine in French Guiana does not require a change in therapeutic recommendations. However, primaquine should be administered more frequently to limit the spread of resistance, and there is still a need for a reliable molecular marker to facilitate the monitoring of P. vivax resistance to chloroquine.

Overview of chemistry and therapeutic potential of non-nitrogen heterocyclics as anticonvulsant agents

2021 ◽  
Vol 19 ◽  
Author(s):  
Rohit Pal ◽  
Karanvir Singh ◽  
Joyson Paul ◽  
Shah Alam Khan ◽  
Mohd. Javed Naim ◽  
...  
Keyword(s):  
Low Income ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Well Being ◽  
Pharmacokinetic Profile ◽  
Heterocyclic Ring ◽  
World Health ◽  
Low Income Countries ◽  
Health Organization ◽  
Nitrogen Heterocyclic

: Epilepsy is a chronic neurological disorder, characterized by predisposition of unprovoked seizures affecting the neurobiological, psychological, cognitive, economic, and social well-being of patient. As per the 2019 report by World Health Organization, it affects nearly 80% of the population which comes from the middle to low-income countries. It has been suggested that 70% of such cases can be treated effectively if properly diagnosed. It is one of the most common neurological diseases affecting 50 million people globally. Most of the antiepileptic drugs used in clinical practice are only 60-80% effective in controlling the disease. These drugs suffer from serious drawbacks of non-selectivity and toxicity that limit their clinical usefulness. Hence, there is a need to search for the safe, potent, and effective anti-epileptic drugs. One of the emerging strategies to discover and develop selective and non-toxic anticonvulsant molecule focuses on design of non-nitrogen heterocyclic compounds (NNHC). Drugs such as valproic acid, gabapentin, viagabatrin, fluorofelbamate, tiagabine, progabide, pregabalin, gamma amino butyric acid (GABA) etc., do not contain a nitrogen heterocyclic ring but are as effective anticonvulsants as conventional heterocyclic nitrogen compounds. This review covers the various classes of NNHC which have been developed in the recent past as anticonvulsants along with their chemistry, percentage yield, structure activity relationship and biological activity. The most potent compound in each series has been identified for the comparative studies, for further structural modification and to improve the pharmacokinetic profile. Various optimized synthetic pathways and diverse functionalities other than nitrogen-containing rings discussed in the article may help medicinal chemists to design safe and effective anticonvulsant drugs in near future.

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