Isatin Derivatives with Potential Antitubercular Activities

Tuberculosis is a life‐threatening chronic infectious disease, which primarily affects the lungs but can spread to other vital organs. The re‐emergence and wide spread of new virulent forms of Mycobacterium tuberculosis that are resistant to some or all first and second line antitubercular agents has reached an alarming level in recent decades. Thus, it is imperative to develop more effective agents. Isatin derivatives are endowed with diverse biological properties, therefore thousands of isatin derivatives have been synthesized in hopes of discovering new candidates with potential antitubercular activities against both drug‐susceptible and drug‐resistant strains. This review summarizes the recent developments of isatin derivatives with potential antitubercular activities.     

Novel Synthetic Routes to Prepare Biologically Active Quinoxalines and Their Derivatives: A Synthetic Review for the Last Two Decades

Quinoxalines, a class of N-heterocyclic compounds, are important biological agents, and a significant amount of research activity has been directed towards this class. They have several prominent pharmacological effects like antifungal, antibacterial, antiviral, and antimicrobial. Quinoxaline derivatives have diverse therapeutic uses and have become the crucial component in drugs used to treat cancerous cells, AIDS, plant viruses, schizophrenia, certifying them a great future in medicinal chemistry. Due to the current pandemic situation caused by SARS-COVID 19, it has become essential to synthesize drugs to combat deadly pathogens (bacteria, fungi, viruses) for now and near future. Since quinoxalines is an essential moiety to treat infectious diseases, numerous synthetic routes have been developed by researchers, with a prime focus on green chemistry and cost-effective methods. This review paper highlights the various synthetic routes to prepare quinoxaline and its derivatives, covering the literature for the last two decades. A total of 31 schemes have been explained using the green chemistry approach, cost-effective methods, and quinoxaline derivatives’ therapeutic uses.     

Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety,Privileged Hybrids in Anticancer Drug Discovery

Pentacyclic triterpenoids are well-known phytochemicals with various biological activities commonly found in plants as secondary metabolites. The wide range of biological activities exhibited by triterpenoids has made them the most valuable sources of pharmacological agents. A number of novel triterpenoid derivatives with many skeletal modifications have been developed. The most important modifications are the formation of analogues or derivatives with nitrogen-containing heterocyclic scaffolds. The derivatives with nitrogen-containing heterocyclic compounds are among the most promising candidate for the development of novel therapeutic drugs. About 75% of FDA-approved drugs are nitrogen-containing heterocyclic moieties. The unique properties of heterocyclic compounds have encouraged many researchers to develop new triterpenoid analogous with pharmacological activities. In this review, we discuss recent advances of nitrogen-containing heterocyclic triterpenoids as potential therapeutic agents. This comprehensive review will assist medicinal chemists to understand new strategies that can result in the development of compounds with potential therapeutic efficacy.     

Design,Synthesis and Biological Evaluation of N-phenylindole Derivatives as Pks13 Inhibitors againstMycobacterium tuberculosis

Polyketide synthase 13 (Pks13), an essential enzyme for the survival of Mycobacterium tuberculosis (Mtb), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against Mtb. The crystallography studies demonstrated that the two-position phenol was solvent-exposed in the Pks13-TE crystal structure and a crucial hydrogen bond was lost while introducing bulkier hydrophobic groups at indole N moieties. Thirty-six N-phenylindole derivatives were synthesized and evaluated for antitubercular activity using a structure-guided approach. The structure–activity relationship (SAR) studies resulted in the discovery of the potent Compounds 45 and 58 against Mtb H37Rv, with an MIC value of 0.0625 μg/mL and 0.125 μg/mL, respectively. The thermal stability analysis showed that they bind with high affinity to the Pks13-TE domain. Preliminary ADME evaluation showed that Compound 58 displayed modest human microsomal stability. This report further validates that targeting Pks13 is a valid strategy for the inhibition of Mtb and provides a novel scaffold for developing leading anti-TB compounds.     

Strecker reaction and α-amino nitriles: Recent advances in their chemistry,synthesis, and biological properties

α-Amino nitrile compounds have a profound impact on bio-chemical sciences, as they have been prepared from inexpensive starting materials and have become valuable intermediates in the chemical synthesis of vitally important heterocyclic and carbocyclic molecules, which serve as suitable models in pharmacological and biological research. The α-amino nitrile moiety has been found in the structure of different alkaloids, while the α-amidoacetonitrile group is an essential fragment of new anti-hyperglycemic drugs and promising pharmacological and agrochemical agents. Due to their synthetic, biological and practical importance, this review highlights the recent information about the preparation of α-amino nitriles through the Strecker-type and α-cyanation reactions, their chemical and biological properties, as well as their synthetic application, paying attention on the wonderful capacity for generating novel molecular diversity for pharmacological, biological and agrochemical researches, which ends with the total synthesis of complex alkaloids, preparation of new N-heterocycles and α-aminonitrile-containing drugs. Analyzing modern synthetic protocols for the Strecker-type reactions and cyanation reactions based on cross-dehydrogenative coupling (CDD) process, the advantages and disadvantages of new catalysts and green reaction conditions are also discussed. In addition, remarkable biological properties of α-amidoacetonitrile derivatives as potent and selective protease inhibitors as well as promising pesticidal agents were briefly reviewed. The bibliography includes 461 references.     

1,3-Oxazole-isoniazid hybrids: Synthesis,antitubercular activity,and their docking studies

A series of novel N′-([2-aryl-5-methyl-1,3-oxazole-4-yl]methylene)isonicotino/nicotino hydrazides 10a-l were prepared by the condensation reaction of 2-aryl-5-methyl-1,3-oxazole-4-carbaldehydes 8a-f with the corresponding isonicotino/nicotino hydrazides 9a/9b . The structures of the new compounds were elucidated by various spectroanalytical techniques, including IR, ¹H NMR, ¹³C NMR, elemental (C,H,N), and mass analysis. All the newly prepared INH-1,3-oxazole hybrids were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. Among all the synthesized hybrids, compounds 10c and 10i derivatives displayed highest antitubercular activity with minimal inhibitory concentration 1.56 μg/mL. Further, molecular docking studies against the InhA enzyme were carried out to understand the interactions between potent hybrids and the target enzyme. Thus, these kind hybrids have the potentiality for the discovery of new antitubercular agents for deployment in the control and eradication of tuberculosis.     

Synthesis,antitubercular evaluation and molecular docking studies of phthalimide bearing 1,2,3-triazoles

In a search for safer and potent antitubercular agents, here a library of newly substituted dioxoisoindolinylmethyl-triazolyl-N-phenylacetamide derivatives (5a–l) has been synthesized via click chemistry approach. All synthesized compounds were evaluated for their antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB). Among the screened compounds, 5d, 5e, 5h, and 5l showed good antitubercular activity. The compounds 5d and 5l have shown very effective antitubercular activity against Mycobacterium tuberculosis H₃₇Rv (MTB) with MIC 12.5?μg/mL. All the newly synthesized compounds were thoroughly characterized by ¹H NMR, ¹³C NMR, and HRMS spectral data. We further performed exploratory docking studies on the crystal structure of Mycobacterium tuberculosis enoyl reductase to demonstrate the mechanism of antitubercular activity.     

QSAR and docking studies on chalcone derivatives for antitubercular activity against M. tuberculosis H37Rv

In our prior studies, we reported some known antitubercular drugs (rifampicin and streptomycin) and newly synthesized chalcone derivatives (16–26) tested in vitro against Mycobacterium tuberculosis H₃₇Rv strain. Most of the tested compounds were efficient antimycobacterial agents showing minimum inhibitory concentration values ranging from 3.5 to 30 µg mL⁻¹. In the present work, a quantitative structure–activity relationship (QSAR) study has been performed on these active chalcone derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. A QSAR model that is able to correlate well the antitubercular activity with the chemical structures of active chalcone derivatives 16, 24, 25a, 25c, and 26 has been developed, which is potentially helpful in the design of novel and more potent antitubercular agents. The r² and rCV² of a newly derived QSAR model were 0.89 and 0.84, respectively. The QSAR study indicates that chemical properties, viz. heat of formation (kcal mol⁻¹), lowest unoccupied molecular orbital energy (eV), and amine, hydroxyl, and methyl groups counts, correlate well with the activity. In silico screening results for oral bioavailability and absorption, distribution, metabolism, excretion, and toxicity compliance showed that compounds 25a, 25c, and 24 were found active similar to rifampicin and streptomycin. The docking study for the exploration of mechanism of action showed high binding affinity of active derivatives. Copyright © 2014 John Wiley & Sons, Ltd.     

Promising Lead Compounds in the Development of Potential Clinical Drug Candidate for Drug-Resistant Tuberculosis

According to WHO report, globally about 10 million active tuberculosis cases, resulting in about 1.6 million deaths, further aggravated by drug-resistant tuberculosis and/or comorbidities with HIV and diabetes are present. Incomplete therapeutic regimen, meager dosing, and the capability of the latent and/or active state tubercular bacilli to abide and do survive against contemporary first-line and second line antitubercular drugs escalate the prevalence of drug-resistant tuberculosis. As a better understanding of tuberculosis, microanatomy has discovered an extended range of new promising antitubercular targets and diagnostic biomarkers. However, there are still no new approved antitubercular drugs of routine therapy for several decades, except for bedaquiline, delamanid, and pretomanid approved tentatively. Despite this, innovative methods are also urgently needed to find potential new antitubercular drug candidates, which potentially decimate both latent state and active state mycobacterium tuberculosis. To explore and identify the most potential antitubercular drug candidate among various reported compounds, we focused to highlight the promising lead derivatives of isoniazid, coumarin, griselimycin, and the antimicrobial peptides. The aim of the present review is to fascinate significant lead compounds in the development of potential clinical drug candidates that might be more precise and effective against drug-resistant tuberculosis, the world research looking for a long time.     

Pharmacological Insights into Halophyte Bioactive Extract Action on Anti-Inflammatory,Pain Relief and Antibiotics-Type Mechanisms

The pharmacological activities in bioactive plant extracts play an increasing role in sustainable resources for valorization and biomedical applications. Bioactive phytochemicals, including natural compounds, secondary metabolites and their derivatives, have attracted significant attention for use in both medicinal products and cosmetic products. Our review highlights the pharmacological mode-of-action and current biomedical applications of key bioactive compounds applied as anti-inflammatory, bactericidal with antibiotics effects, and pain relief purposes in controlled clinical studies or preclinical studies. In this systematic review, the availability of bioactive compounds from several salt-tolerant plant species, mainly focusing on the three promising species Aster tripolium, Crithmum maritimum and Salicornia europaea, are summarized and discussed. All three of them have been widely used in natural folk medicines and are now in the focus for future nutraceutical and pharmacological applications.     

Oxidative Cyclization of Isoniazid with Fluoroquinolones: Synthesis,Antibacterial and Antitubercular Activity of New 2,5‐disubstituted‐1,3,4‐Oxadiazoles

We report herein one‐pot synthesis and the antibacterial and antitubercular activities of 2,5‐disubstituted‐1,3,4‐oxadiazole compounds obtained by hybridization of a well‐known antitubercular agent isoniazid (INH ) with four broad‐spectrum antibiotics belonging to fluoroquinolone (FQ ) class. The work is aimed at designing and developing potential antimicrobial agents having synergistic action due to the coupling of INH and FQ through the biologically active 1,3,4‐oxadiazole nucleus. The synthesized compounds are expected to have low toxicity as compared to INH due to the absence of free hydrazide group in the chemical structure of the prepared derivatives. The antibacterial activities of the 1,3,4 oxadiazole derivatives were also tested against several Gram‐positive and Gram‐negative pathogenic bacterial strains. The antitubercular activity was evaluated against M. tuberculosis H₃₇Rv strain, and the results were compared with that of the positive control INH . The title compounds showed excellent antimicrobial and promising antitubercular activity in comparison to the parent fluoroquinolones and INH , respectively.     

Synthesis,Biological Evaluation,and In Silico Studies of New Acetylcholinesterase Inhibitors Based on Quinoxaline Scaffold

A quinoxaline scaffold exhibits various bioactivities in pharmacotherapeutic interests. In this research, twelve quinoxaline derivatives were synthesized and evaluated as new acetylcholinesterase inhibitors. We found all compounds showed potent inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values of 0.077 to 50.080 µM, along with promising predicted drug-likeness and blood–brain barrier (BBB) permeation. In addition, potent butyrylcholinesterase (BChE) inhibitory activity with IC₅₀ values of 14.91 to 60.95 µM was observed in some compounds. Enzyme kinetic study revealed the most potent compound (6c) as a mixed-type AChE inhibitor. No cytotoxicity from the quinoxaline derivatives was noticed in the human neuroblastoma cell line (SHSY5Y). In silico study suggested the compounds preferred the peripheral anionic site (PAS) to the catalytic anionic site (CAS), which was different from AChE inhibitors (tacrine and galanthamine). We had proposed the molecular design guided for quinoxaline derivatives targeting the PAS site. Therefore, the quinoxaline derivatives could offer the lead for the newly developed candidate as potential acetylcholinesterase inhibitors.     

An overview on novel synthetic approaches and medicinal applications of benzimidazole compounds

Benzimidazole, a benzene-fused heterocyclic compound, has acquired significant attention in the field of contemporary medicinal chemistry because of its wide array of pharmacological activities. Nitrogen containing heterocyclic compounds are part of several therapeutically important agents with several recent patents shedding light on their worth. For these reasons, this review is concerned with different methods for synthesis of benzimidazole derivatives and their biological importance.     

Synthesis and Antitubercular Evaluation of N‐Arylpyrazine and N,N′‐Alkyl‐diylpyrazine‐2‐carboxamide Derivatives

Two series of pyrazinamide (PZA) derivatives have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv. Some compounds exhibited minimum inhibitory concentration activity of 50–100 μg/mL, greater than the first line antituberculosis drug PZA in Alamar Blue assay (>100 μg/mL). The obtained activities can be considered promising results, which characterizes these compounds as good start points to development of new antitubercular agents.     

Study of physicochemical properties-antitubercular activity relationship of naphthalene-1,4-dione analogs: A QSAR approach

Enduring pandemic nature of tuberculosis urges to explore novel antimycobacterial agents with different mechanism of actions. Plant containing 1,4-naphthoquinone derivatives showed promising antitubercular activity with novel mode of action and their synthetic/semi-synthetic derivatives devoid of toxicity. Structural requirements of naphthalene-1,4-dione derivatives towards antitubercular activity and cytotoxicity were explored using a mathematical model in order to understand their physicochemical parameters. A quantitative structure activity relationship study furnished some important structural insights for antitubercular activity, i.e. average connectivity index, information content index of neighborhood symmetry, aromatic ratio, and path/walk 3 Randic shape index. Similarly it also provides drivers for the cytotoxicity of compounds. These drivers will be helpful in further development of safer and potent 1,4-naphthoquinone derivatives.     

Quinoline Derivatives with Potential Activity Against Multidrug‐resistant Tuberculosis

Tuberculosis (TB), which affects primarily the lungs (pulmonary TB) apart from other vital organs, is a life‐threatening chronic deadliest infectious disease caused by members of Mycobacterium tuberculosis (MTB) complex and mainly by MTB itself. The emergence of MTB new virulent forms that are resistant to some or all first‐line and second‐line anti‐TB agents, including multidrug‐resistant (MDR), extensively drug‐resistant, and totally drug‐resistant strains has further aggravated the spread of this disease and was increased up to an alarming level in the recent decades. More than ever, it is imperative to develop novel, high effective, and fast acting anti‐TB drugs to prevent the spread of TB, particularly in its hard‐to‐kill MDR‐TB, extensively drug‐resistant‐TB, and totally drug‐resistant‐TB strains. In recent years, numerous compounds have been synthesized for this purpose, but only a handful of compounds have entered human trials after the discovery of rifampicin, reflecting the inherent difficulties of developing new anti‐TB agents. Despite of bedaquiline and delamanid have received approval from many countries for treatment of MDR‐TB infected patients, both drugs are associated with serious side effects and are only recommended for those MDR‐TB patients without other treatment options. All these aforementioned facts make it an urgent need to develop novel drugs. Quinoline‐based derivatives including quinolones ex biological activities, and some of them displayed excellent in vitro and in vivo activities against MDR‐TB. This review outlines the recent developments of quinoline‐based derivatives with potential activity against MDR‐TB as well as the structure–activity relationship.     

Efficient regioselective heterocyclisation leading to fluorescent fused pyrazine derivatives

The regioselective syntheses of substituted pyrrolo[2,3-b]quinoxaline, pyrido[2,3-b]pyrrolo[2,3-e]pyrazine, pyrido[2,3-b]pyrrolo[3,2-e]pyrazine and pyrido[3,4-b]pyrrolo[3,2-e]pyrazine are reported. Differential reactivity between two amino groups in ortho-diaminopyridine can be exploited to obtain new regio-defined unsymmetrical pyridopyrrolopyrazine derivatives. Weak electron-donating methyl or moderately electron-withdrawing carboxylic groups attached to the aromatic ortho-diamines reduce the regioselectivity of obtaining unsymmetrical substituted pyrrolo[2,3-b]quinoxaline. The fluorescence properties of the resultant 1-alkyl pyridopyrrolopyrazine and substituted pyrrolo[2,3-b]quinoxaline derivatives are presented.     

Novel 5H-[1,2,4]oxadiazolo[4,5-a]pyrimidin-5-one derivatives as antibacterial and anticancer agents: Synthesis and biological evaluation

A novel class of 5H-[1,2,4]oxadiazolo[4,5-a]pyrimidine derivatives was prepared, characterized, and tested for its antibacterial and anticancer potential against thirteen strains and five human cancer cell lines. The synthetic method was optimized, and a proposed reaction mechanism was also presented. The compounds containing the 5-bromo-pyrimidine moiety exhibited moderate antibacterial potencies against Gram-positive strains. Furthermore, the newly prepared compounds displayed selectively antiproliferative activity against human cancer cell lines. These current results will help us to further optimize and develop new drug candidates for clinical studies as novel antibacterial or anticancer agents.     

Comparisons of Isolation Methods,Structural Features,and Bioactivities of the Polysaccharides from Three Common Panax Species: A Review of Recent Progress

Panax spp. (Araliaceae family) are widely used medicinal plants and they mainly include Panax ginseng C.A. Meyer, Panax quinquefolium L. (American ginseng), and Panax notoginseng (notoginseng). Polysaccharides are the main active ingredients in these plants and have demonstrated diverse pharmacological functions, but comparisons of isolation methods, structural features, and bioactivities of these polysaccharides have not yet been reported. This review summarizes recent advances associated with 112 polysaccharides from ginseng, 25 polysaccharides from American ginseng, and 36 polysaccharides from notoginseng and it compares the differences in extraction, purification, structural features, and bioactivities. Most studies focus on ginseng polysaccharides and comparisons are typically made with the polysaccharides from American ginseng and notoginseng. For the extraction, purification, and structural analysis, the processes are similar for the polysaccharides from the three Panax species. Previous studies determined that 55 polysaccharides from ginseng, 18 polysaccharides from American ginseng, and 9 polysaccharides from notoginseng exhibited anti-tumor activity, immunoregulatory effects, anti-oxidant activity, and other pharmacological functions, which are mediated by multiple signaling pathways, including mitogen-activated protein kinase, nuclear factor kappa B, or redox balance pathways. This review can provide new insights into the similarities and differences among the polysaccharides from the three Panax species, which can facilitate and guide further studies to explore the medicinal properties of the Araliaceae family used in traditional Chinese medicine.