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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.

Human tuberculosis (TB) is primarily caused by Mycobacterium tuberculosis (Mtb) that inhabits inside and amidst immune cells of the host with adapted physiology to regulate interdependent cellular functions with intact pathogenic potential. The complexity of this disease is attributed to various factors such as the reactivation of latent TB form after prolonged persistence, disease progression specifically in immunocompromised patients, advent of multi- and extensivelydrug resistant (MDR and XDR) Mtb strains, adverse effects of tailor-made regimens, and drug-drug interactions among anti-TB drugs and anti-HIV therapies. Thus, there is a compelling demand for newer anti-TB drugs or regimens to overcome these obstacles. Considerable multifaceted transformations in the current TB methodologies and molecular interventions underpinning hostpathogen interactions and drug resistance mechanisms may assist to overcome the emerging drug resistance. Evidently, recent scientific and clinical advances have revolutionised the diagnosis, prevention, and treatment of all forms of the disease. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs.

A series of some novel (E)-2-methyl/propyl-4-[(2-(substitutedbenzylidene)hydrazinyl]-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines was synthesized and characterized by adopting an appropriate synthetic scheme. The effect of electron withdrawing and electron donating groups at the aromatic ring in presence of methyl and propyl substituents at the 2-position of the scaffold was evaluated for anthelmintic activity against adult Indian earthworms (Pheretima posthuma). Among 2-methyl-thieno[2,3-d]pyrimidine analogs, compounds with electron donating methoxy group either at para-position or at meta and para-positions of the aromatic ring showed potent anthelmintic activity at 100 μg/ml (284 and 261.8 μM concentrations) for compounds 5g and 5h with a mean paralytic time of 2.32, 2.22 min, and helminthicidal time of 22.38, 19.43 min, respectively. In contrast, the presence of electron withdrawing chloro group at ortho and para-position of the aromatic ring was found to be favorable for the anthelminthic activity of the compounds 5n and 5o (at concentration of 259.7 μM) with propyl group at the 2-position of the thieno[2,3-d]pyrimidine scaffold, exhibiting mean paralytic time of 2.5 min, 2.81 min and helminthicidal time of 21, 20.03 min, respectively. Anthelmintic activities of these four compounds 5g, 5h, 5n, and 5o (at the concentrations of 284, 261.8, 259.7, and 259.7 μM, respectively) were found to be on par with the standard drug piperazine adipate (time for paralysis and death at 6.25 and 24.5 min, respectively) at concentration of 100 μg/ml (431.03 μM). Overall, the potency of these compounds (5g, 5h, 5n, and 5o) is better than standard drug as they exhibited the same activity at 259.7–284 μM as that of a standard drug (which has shown the same activity at 431.03 μM). Further, the predicted ADME properties of all the synthesized compounds were found to be in the satisfactory ranges as predicted by SwissADME software and found to have drug-like properties. Thus, further modification of these compounds might lead to the discovery of more potent analogs.

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a–e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

Tuberculosis (TB) is a communicable airborne infectious disease caused by the Mycobacterium tuberculosis (MTB) that primarily affects the lungs, and can disseminate to other parts of the body. MTB is one of the most dangerous pathogens, killing about 1.4 million people annually worldwide. Although the standard treatment of TB is comprised of four anti-TB drugs, the emergence of multidrug-resistant (MDR) and extensive drug-resistant (XDR) strains in the recent past and associated side effects have affected the tailor-made regimens. Notably, existing therapies approved by the World Health Organisation (WHO) can only treat less than 50% of drug-resistant TB. Therefore, an expeditious pace in the TB research is highly needed in search of effective, affordable, least toxic novel drugs with shorter regimens to reach the goals viz. 2020 milestones End TB strategy set by the WHO. Currently, twenty-three drug-like molecules are under investigation in different stages of clinical trials. These newer agents are expected to be effective against the resistant strains. This article summarizes the properties, merits, demerits, and the probability of their success as novel potential therapeutic agents.

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.

A series of ethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-3-carboxylates 4a&ndash, f and dimethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylates 4g&ndash, k have been synthesized and evaluated for their anti-tubercular (TB) activities against H37Rv (American Type Culture Collection (ATCC) strain 25177) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis by resazurin microplate assay (REMA). Molecular target identification for these compounds was also carried out by a computational approach. All test compounds exhibited anti-tuberculosis (TB) activity in the range of 8&ndash, 128 &micro, g/mL against H37Rv. The test compound dimethyl-1-(4-fluorobenzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylate 4j emerged as the most promising anti-TB agent against H37Rv and multidrug-resistant strains of Mycobacterium tuberculosis at 8 and 16 &micro, g/mL, respectively. In silico evaluation of pharmacokinetic properties indicated overall drug-likeness for most of the compounds. Docking studies were also carried out to investigate the binding affinities as well as interactions of these compounds with the target proteins.

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.

Adenosine is an endogenous nucleoside molecule, regulating a myriad of physiological and pathological effects in almost all the organs systems including central nervous system (CNS), cardiovascular system (CVS), respiratory system, renal system, and immune system. Biological functions of adenosine are mediated by its interactions with four subtypes of G-protein-coupled receptors (GPCRs), namely A1, A2A, A2B, and A3 adenosine receptors (ARs) which are ubiquitously present throughout the body. However, ubiquitous distribution of ARs in both healthy and diseased tissues imposed a great challenge to the researchers in the discovery and development of ligands targeting a particular AR subtype in a specific tissue, devoid of undesirable side effects. This chapter provides an overview of the synthesis, metabolism, and cellular transport of adenosine, with particular emphasis on the distribution and signaling mechanisms of ARs, including specific examples of agonists/partial agonists, antagonists, and allosteric modulators of ARs as potential therapeutic agents.

Acetylcholine is a neurotransmitter that plays a significant role in a variety of physiological functions. Cholinergic neurons synthesize, store, and release acetylcholine and are also responsible for sympathetic and parasympathetic responses of the autonomous nervous system. The wide range of functions that the cholinergic system plays explains the diverse range of therapeutic potential that targets this system. Over the decades, cholinergic and anticholinergic drugs are utilized as treatment options for various conditions including ophthalmology, neurogenic bladder, myasthenia gravis, dementia, postoperative urinary retention, xerostomia, anticholinergic overdose, snakebites, Parkinson’s disease, and Alzheimer’s disease. Alongside, they are also investigated for various promising therapeutics. This chapter provides an overview of the cholinergic system pharmacology, functions in the body, cholinergic and anticholinergic compounds, and their potential role in the medical field. Further, the chapter highlights the updates on the cholinergic compounds currently used to treat various conditions as well as compounds under investigation.

Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.

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.

A series of novel 7-amino-5-oxo-2-substituted-aryl/hetero-aryl-5,8-dihydro[1,2,4]triazolo[1,5-a]pyridine-6-carbonitriles (4a-4t) was synthesized, characterized and evaluated for their binding affinity and selectivity towards hA1 , hA2A , hA2B and hA3 adenosine receptors (ARs). Compound 4a with a phenyl ring at 2-position of the triazolo moiety of the scaffold showed high affinity and selectivity for hA1 AR (Ki hA1 = 0.076 μM, hA2A = 25.6 μM and hA3 > 100 μM). Introduction of various electron donating and withdrawing groups at different positions of the phenyl ring resulted in drastic reduction in affinity and selectivity towards all the ARs, except compound 4b with a 4-hydroxyphenyl group at 2-position. Interestingly, the replacement of the phenyl ring with a smaller heterocyclic thiophene ring (π excessive system) resulted in further improvement of affinity for hA1 AR of compound 4t (Ki hA1 = 0.051 μM, hA2A = 9.01 μM and hA3 > 13.9 μM) while retaining the significant selectivity against all other AR subtypes similar to compound 4a. The encouraging results for compounds 4a and 4t indicate that substitution at 2-position of the scaffold with π-excessive systems other than thiophene may lead to even more potent and selective hA1 AR antagonists.

A rapid synthesis of a series of new 5,6-dimethyl-7-phenyl-2-alkyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinones and 5,6-dimethyl-7-benzyl-2-alkyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinones was accomplished in good yields using microwave irradiation under base catalysis.

A series of alkyl- and aryl-1,2,4-triazino[4,3-c]quinazolines (5a-h and 8a-h) were synthesized and characterized. The title compounds were evaluated for their in vivo bronchodilator activity on guinea pigs. All the test compounds exhibited good protection against histamine-induced bronchospasm. The structure-activity relationships based on the results obtained for these series were studied. Incorporation of an aryl ring with halo substitution to the theophylline bioisostere increases its potency. Among the compounds tested, 5b was found to be the most potent with 88.7% protection against histamine-induced bronchospasm compared to the standard compound aminophylline (87.8%).

A rapid synthesis of a series of new 5,6-dimethyl-7-phenyl-2-alkyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinones and 5,6-dimethyl-7-benzyl-2-alkyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidinones was accomplished in good yields using microwave irradiation under base catalysis.