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Abstract: Icacinaceae, an Angiospermic family comprising 35 genera and 212 accepted species, including trees, shrubs, and lianas with pantropical distribution, is one of the most outshining yet least explored plant families, which despite its vital role as a source of pharmaceuticals and nutraceuticals has received a meagre amount of attraction from the scientific community. Interestingly, Icacinaceae is considered a potential alternative resource for camptothecin and its derivatives, which are used in treating ovarian and metastatic colorectal cancer. However, the concept of this family has been revised many times, but further recognition is still needed. The prime objective of this review is to compile the available information on this family in order to popularize it in the scientific community and the general population and promote extensive exploration of these taxa. The phytochemical preparations or isolated compounds from the Icacinaceae family have been centrally amalgamated to draw diverse future prospects from this inclusive plant species. The ethnopharmacological activities and the associated endophytes and cell culture techniques are also depicted. Nevertheless, the methodical evaluation of the Icacinaceae family is the only means to preserve and corroborate the folkloristic remedial effects and provide scientific recognition of its potencies before they are lost under the blanket of modernization.

Malaria is a serious worldwide medical issue that results in substantial annual death and morbidity. The availability of treatment alternatives is limited, and the rise of resistant parasite types has posed a significant challenge to malaria treatment. To prevent a public health disaster, novel antimalarial agents with single-dosage therapies, extensive curative capability, and new mechanisms are urgently needed. There are several approaches to developing antimalarial drugs, ranging from alterations of current drugs to the creation of new compounds with specific targeting abilities. The availability of multiple genomic techniques, as well as recent advancements in parasite biology, provides a varied collection of possible targets for the development of novel treatments. A number of promising pharmacological interference targets have been uncovered in modern times. As a result, our review concentrates on the most current scientific and technical progress in the innovation of new antimalarial medications. The protein kinases, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, isoprenoid biosynthesis inhibitors, and enzymes involved in the metabolism of lipids and replication of deoxyribonucleic acid, are among the most fascinating antimalarial target proteins presently being investigated. The new cellular targets and drugs which can inhibit malaria and their development techniques are summarised in this study.

As of September 2021, 117 COVID-19 vaccines are in clinical development, and 194 are in preclinical development as per the World Health Organization (WHO) published draft landscape. Among the 117 vaccines undergoing clinical trials, the major platforms include protein subunit; RNA; inactivated virus; viral vector, among others. So far, USFDA recognized to approve the Pfizer-BioNTech (Comirnaty) COVID-19 vaccine for its full use in individuals of 16 years of age and older. Though the approved vaccines are being manufactured at a tremendous pace, the wealthiest countries have about 28% of total vaccines despite possessing only 10.8% of the total world population, suggesting an inequity of vaccine distribution. The review comprehensively summarizes the history of vaccines, mainly focusing on vaccines for SARS-CoV-2. The review also connects relevant topics, including measurement of vaccines efficacy against SARS-CoV-2 and its variants, associated challenges, and limitations, as hurdles in global vaccination are also kept forth.

A series of 1,2,3-trisubstituted indolizines (2a–2f, 3a–3d, and 4a–4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b–2d, 3a–3d, and 4a–4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a–4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16–64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.

The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives (3a–3i) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively. To understand the mechanism of action of these compounds (3a–3i) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a, promising leads worthy of further optimisation.

Background: Recently, a series of 15 compounds with 2,4,5-trisubstitutedthiazole scaffold having 2- amino/amido/ureido functional groups attached with 5-aryl and 4-carboxylic acid/ester groups (1-15) were reported from our research group as novel potential inhibitors of carbonic anhydrase III (CA III) enzyme. Several research studies revealed the potential role of CA inhibitors as anticancer agents, giving us the impetus to further explore these compounds for their potential as anticancer agents. Objectives: The objective of this study is to investigate the potential of 2,4,5-trisubstitutedthiazole derivatives (1-15) for their possible cytotoxic activity (in vitro), and to calculate (in silico) the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties to evaluate the drug-likeness of these compounds. Methods: Cytotoxic activity (in vitro) was carried out on two breast cancer cell lines (MCF7 and MDA231), and the lymphoblastoid human erythroleukemia cell line (K562) using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Doxorubicin was used as a positive control. ADMET properties were calculated (in silico) using the QikProp module of Schrodinger. Results: Compounds 6 and 9 with a phenylureido group at 2-position, and a methyl-carboxylate moiety at 4-position having para-tolyl and benzyl moiety, respectively at the 5-position of the thiazole ring showed significant cytotoxicity against all the three cell lines. In particular, compound 6 with para-tolyl group at 5-position exhibited the most potent inhibitory effect on the viability of MCF7, MDA231 and K562 cells, with IC50 values of 22, 26 and 11 μM, respectively. Notably, all the highly active compounds possess a phenyluriedo group at 2-- position with a methyl ester group at 4-position, indicating the probable role of these substituents in the target interaction and inducing cytotoxicity. Interestingly, compounds 1-4 and 10-13 with a free amino group at 2-position did not show any cytotoxic effect on the K562 cell line, while exhibiting mild to moderate cytotoxicity against the MCF7 and MDA231 cell lines. However, none of the tested compounds showed any activity against normal human dermal fibroblast cells indicating the safety/tolerability of the examined concentrations. Furthermore, these compounds also exhibited satisfactory ADMET properties (in silico), without violating Lipinski’s rule of five. Conclusion: The most active compounds 6 and 9 predicted to have good oral absorption and low human serum protein binding, exhibiting no reactive functional group and probable CNS activity compared with 95% of the known oral drugs as predicted (in silico) by QikProp. Thus, compounds 6 and 9 can be considered as lead molecules for further modification and discovery of novel anticancer agents with nanomolar potency.

In the drug discovery setting, undesirable ADMET properties of a pharmacophore with good predictive power obtained after a tedious drug discovery and development process may lead to late-stage attrition. The earlystage ADMET profiling has brought a new dimension to lead drug development. Although several high-throughput in vitro models are available for ADMET profiling, the in silico methods are gaining more importance because of their economic and faster prediction ability without the requirements of tedious and expensive laboratory resources. Nonetheless, in silico ADMET tools alone are not accurate, and therefore, ideally adopted along with in vitro and or in vivo methods in order to enhance the predictability power. This review summarizes the significance and challenges associated with the application of in silico tools as well as the possible scope of in vitro models for integration to improve the ADMET predictability power of these tools.

The COVID-19 pandemic continues to wreak havoc worldwide due to the lack of risk assessment, rapid spreading ability, and propensity to precipitate severe disease in comorbid conditions. In an attempt to fulfill the demand for prophylactic and treatment measures to intercept the ongoing outbreak, the drug development process is facing several obstacles and renaissance in clinical trials, including vaccines, antivirals, immunomodulators, plasma therapy, and traditional medicines. This review outlines the overview of SARS-CoV-2 infection, significant recent findings, and ongoing clinical trials concerning current and future therapeutic interventions for the management of advancing pandemic of the century.

The successful conversion of natural products (NPs) into lead compounds and novel pharmacophores has emboldened the researchers to harness the drug discovery process with a lot more enthusiasm. However, forfeit of bioactive NPs resulting from an overabundance of metabolites and their wide dynamic range have created the bottleneck in NP researches. Similarly, the existence of multidimensional challenges, including the evaluation of pharmacokinetics, pharmacodynamics, and safety parameters, has been a concerning issue. Advancement of technology has brought the evolution of traditional natural product researches into the computer-based assessment exhibiting pretentious remarks about their efficiency in drug discovery. The early attention to the quality of the NPs may reduce the attrition rate of drug candidates by parallel assessment of ADMET profiling. This article reviews the status, challenges, opportunities, and integration of advanced technologies in natural product research. Indeed, emphasis will be laid on the current and futuristic direction towards the application of newer technologies in early-stage ADMET profiling of bioactive moieties from the natural sources. It can be expected that combinatorial approaches in ADMET profiling will fortify the natural product-based drug discovery in the near future.

The identification of cannabinoid (CB) receptors has contributed to the state-of-the-art on the endocannabinoid system and its elements. Endocannabinoids (eCBs) are the endogenous agonists, derived from the conjugation of arachidonic acid with either ethanolamine (i.e. anandamide) or glycerol (i.e. 2-arachidonoylglycerol) acting as a lipid signaling mediator via two types of cannabinoid receptors (i.e. CB1 and CB2). Introduction of selective CB antagonists, inhibitors of eCB transport and metabolism, cannabinoid receptor-deficient mice and highlights on amidohydrolase have greatly facilitated the subsequent investigation of the eCB system. Moreover, modulation of the eCB system holds a promising therapeutic potential in the management of a myriad of pathophysiological conditions such as anxiety or mood disorders, neuropathic pain, multiple sclerosis, neurodegenerative diseases, osteoporosis, obesity and cancer among others. This chapter is comprehensively focused on the signal transduction and metabolic pathways, physiological roles, pharmacology and therapeutic potential of the endocannabinoids, with particular emphasis on cannabinoid addiction.

Adenosine is a purine nucleoside, responsible for the regulation of a wide range of physiological and pathophysiological conditions by binding with four G-protein-coupled receptors (GPCRs), namely A1, A2A, A2B and A3 adenosine receptors (ARs). In particular, A1 AR is ubiquitously present, mediating a variety of physiological processes throughout the body, thus represents a promising drug target for the management of various pathological conditions. Agonists of A1 AR are found to be useful for the treatment of atrial arrhythmia, angina, type-2 diabetes, glaucoma, neuropathic pain, epilepsy, depression and Huntington’s disease, whereas antagonists are being investigated for the treatment of diuresis, congestive heart failure, asthma, COPD, anxiety and dementia. However, treatment with full A1 AR agonists has been associated with numerous challenges like cardiovascular side effects, off-target activation as well as desensitization of A1 AR leading to tachyphylaxis. In this regard, partial agonists of A1 AR have been found to be beneficial in enhancing insulin sensitivity and subsequently reducing blood glucose level, while avoiding severe CVS side effects and tachyphylaxis. Allosteric enhancer of A1 AR is found to be potent for the treatment of neuropathic pain, culminating the side effects related to off-target tissue activation of A1 AR. This review provides an overview of the medicinal chemistry and therapeutic potential of various agonists/partial agonists, antagonists and allosteric modulators of A1 AR, with a particular emphasis on their current status and future perspectives in clinical settings.

Background:Adenosine mediates various physiological and pathological conditions by acting on its four P1 receptors (A1, A2A, A2B and A3 receptors). Omnipresence of P1 receptors and their activation, exert a wide range of biological activities. Thus, its modulation is implicated in various disorders like Parkinson’s disease, asthma, cardiovascular disorders, cancer etc. Hence these receptors have become an interesting target for the researchers to develop potential therapeutic agents. Number of molecules were designed and developed in the past few years and evaluated for their efficacy in various disease conditions.Objective:The main objective is to provide an overview of new chemical entities which have crossed preclinical studies and reached clinical trials stage following their current status and future prospective.Methods:In this review we discuss current status of the drug candidates which have undergone clinical trials and their prospects.Results:Many chemical entities targeting various subtypes of P1 receptors are patented; twenty of them have crossed preclinical studies and reached clinical trials stage. Two of them viz adenosine and regadenoson are approved by the Food and Drug Administration.Conclusion:This review is an attempt to highlight the current status, progress and probable future of P1 receptor ligands which are under clinical trials as promising novel therapeutic agents and the direction in which research should proceed with a view to come out with novel therapeutic agents.