Exploring the recent pioneering developments of small molecules in antimalarial drug armamentarium: A chemistry prospective appraisal.

Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug-resistant strains. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

Drug reactive metabolite-induced hepatotoxicity: a comprehensive review.

Nowadays, drug-induced liver toxicity (DILT) is one of the main contributing factors to severe liver disease. In the United States (US) alone, DILT is the cause of more than 50% of instances of acute liver failure. Prescription or over-the-counter drugs, xenobiotics, and herbal and nutritional supplements can cause DILT and could produce anomalies in hepatic function tests. Some drugs induce hepatotoxicity directly, and others induce it indirectly (i. e. through their toxic or reactive metabolites). Currently, the United States Food and Drug Administration (US FDA) has issued black box warnings for about 1279 drugs due to their hepatotoxicity. When we analyzed their mechanism in inducing hepatotoxicity, we found nearly 18 drugs causing hepatotoxicity by their toxic metabolites. In this review, we attempted to highlight the well-known drugs that induce hepatotoxicity indirectly through their toxic metabolites including the enzymes involved in the formation of these metabolites. The Cytochrome P-450 (CYP), Hypoxanthine phosphoribosyltransferase 1, Alcohol oxidase, Uridine diphosphate (UDP)-glucuronosyltransferases, Xanthine dehydrogenase, Purine-nucleoside phosphorylase, Xanthine oxidase, Thiopurine S-methyltransferase, Inosine-5'-monophosphate dehydrogenase, and aldehyde dehydrogenase are involving in the formation of toxic metabolites. The metabolic reactions and enzymes discussed in this review help toxicologists, pharmacologists, and chemists to design and develop hepatotoxicity-free pharmaceutical products containing the inhibitors of these enzymes to reduce hepatotoxicity and improve human health.

Nitrosamine Impurities in Pharmaceuticals: An Empirical Review of their Detection, Mechanisms, and Regulatory Approaches.

Since their discovery in valsartan-containing drugs, nitrosamine impurities have emerged as a significant safety problem in pharmaceutical products, prompting extensive recalls and suspensions. Valsartan, candesartan, irbesartan, olmesartan, and other sartans have been discovered to have additional nitrosamine impurities, such as N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso-Di-isopropyl amine (NDIPA), N-nitroso-Ethyl-Isopropyl amine (NEIPA), and N-nitroso-Diethyl amine (NDEA). Concerns about drug safety have grown in response to reports of nitrosamine contamination in pharmaceuticals, such as pioglitazone, rifampin, rifapentine, and varenicline. This review investigates the occurrence and impact of nitrosamine impurities in sartans and pharmaceutical goods, as well as their underlying causes. The discussion emphasizes the significance of comprehensive risk assessment and mitigation approaches at various phases of medication development and manufacturing. The link between amines and nitrosamine impurities is also investigated, with an emphasis on pH levels and the behaviour of primary, secondary, tertiary, and quaternary amines. Regulations defining standards for nitrosamine assessment and management, such as ICH Q3A-Q3E and ICH M7, are critical in resolving impurity issues. Furthermore, the Global Substance Registration System (GSRS) is underlined as being critical for information sharing and product safety in the pharmaceutical industry. The review specifically focuses on the relationship between ranitidine and N-nitroso dimethyl amine (NDMA) in the context of the implications of nitrosamine contamination on patient safety and medicine supply. The importance of regulatory authorities in discovering and correcting nitrosamine impurities is highlighted in order to improve patient safety, product quality, and life expectancy. Furthermore, the significance of ongoing study and attention to nitrosamine-related repercussions for increasing pharmaceutical safety and overall public health is emphasized.

An appraisal of anti-mycobacterial activity with structure-activity relationship of piperazine and its analogues: A review.

Piperazine, is privileged six membered nitrogen containing heterocyclic ring also known as 1,4-Diazacyclohexane. Consequently, piperazine is a versatile medicinally important scaffold and is an essential core in numerous marketed drugs with diverse pharmacological activities. In recent years several potent molecules containing piperazine as an essential subunit of the structural frame have been reported, especially against Mycobacterium tuberculosis (MTB). Remarkably, a good number of these reported molecules also displayed potential activity against multidrug-resistant (MDR), and extremely drug-resistant (XDR) strains of MTB. In this review, we have made a concerted effort to retrace anti-mycobacterial compounds for the past five decades (1971-2019) specifically where piperazine has been used as a vital building block. This review will benefit medicinal chemists as it elaborates on the design, rationale and structure-activity relationship (SAR) of the reported potent piperazine based anti-TB molecules, which in turn will assist them in addressing the gaps, exploiting the reported strategies and developing safer, selective, and cost-effective anti-mycobacterial agents.

Exploring MDR-TB Inhibitory Potential of 4-Aminoquinazolines as Mycobacterium tuberculosis N-Acetylglucosamine-1-Phosphate Uridyltransferase (GlmUMTB ) Inhibitors.

Drug resistance tuberculosis is one of the challenging tasks that dictates the desperate need for the development of new antitubercular agents which operate via novel modes of action. Here, we are reporting on 4-aminoquinazolines as M. tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmUMTB ) inhibitors to overcome the problem of the MDR-TB. Amongst the synthesized compounds, two of them were observed to be the effective compounds of the series (IC50 =6.4 µM (H37Rv), MIC=25 µM (MDR-TB) and IC50 =2.9 µM (H37Rv), MIC=6.25 µM (MDR-TB), respectively).

Synthesis and Biological Evaluation of Novel Carbazole Hybrids as Promising Antimicrobial Agents.

Two series of carbazole analogs of 8-methoxy-N-substituted-9H-carbazole-3-carboxamides (series 1) and carbazolyl substituted rhodanines (series 2) were synthesized through facile synthetic routes. All the final compounds from these two series were evaluated for their preliminary in vitro antifungal and antibacterial activity against four fungal (Candida albicans, Cryptococcus neoformans, Cryptococcus tropicalis and Aspergillus niger) and four bacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) strains, respectively. Among the tested compounds, three compounds of series 1 displayed promising antifungal and antibacterial activity, especially against C. neoformans and S. aureus. In addition, one compound of series 1 displayed notable antimicrobial activity (MIC: 6.25 µg/mL) against clinical isolates of C. albicans and C. neoformans (MIC: 12.5 µg/mL). From the second series, four compounds exhibited significant antifungal and antibacterial activity, especially against C. neoformans and S. aureus. The most active compound of series 2 displayed a prominent antimicrobial activity against C. neoformans (MIC: 3.125 µg/mL) and S. aureus (MIC: 1.56 µg/mL), respectively.

Design, Synthesis, and Characterization of Novel Linomide Analogues and their Evaluation for Anticancer Activity.

BACKGROUND: According to WHO, in 2017, about 90.5 million people suffered from cancer and about 8.8 million deaths occurred due to disease. Although the chemotherapeutic agents have decreased the mortality among the cancer patients but high toxicity and non-specific targets are still major drawbacks. Many researchers have identified linomide, a 4-hydroxy-2-quinolone derivative, as a lead molecule for the development of anticancer agents. With this background, we thought of the following objective. OBJECTIVE: The objective of this research work involves the synthesis of a series of N-(2-(4- hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides IVa-d (1-3) by replacing the anilide moiety at the third position of linomide with sulfamoylacyl and also N-methyl by N-phenyl functionality. To perform in silico anticancer activity by using Molegro Virtual Docker (MVD-2013, 6.0) software and in vitro anticancer activity by MTT assay. METHODS: The starting material 4-hydroxy-1-phenylquinolin-2(1H)-one was treated with N-bromosuccinamide to yield compound II. Condensation of compound II with primary amines resulted in compounds IIIa-d, which, on coupling with substituted aromatic sulfonyl chlorides yield the title compounds IVa-d (1-3). RESULTS: All the synthesized compounds were satisfactorily characterized by spectral data. The results of docking revealed that the synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17). The MolDock Score of compound IVd-1 (-115.503) was the highest amongst those tested. The in vitro anticancer activity results showed that compound IVc-1 (R= - (CH2) 2-CH3 ; R'= -H) and IV d-1 (R= -CH2-C6H5; R'= -H) were found to be most potent against K562 cell line with an IC50 of 0.451 µM/ml and 0.455 µM/ml respectively. Compound IVd-1 also showed better potency against A549 cell line with IC50 value of 0.704 µM/ml. CONCLUSION: The results of in silico and in vitro anticancer activity are in agreement with each other. Compound IV d-1 was found to be most active of the series.

Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA.

InhA (Enoyl-ACP reductase) plays a crucial role in the biosynthetic pathway of cell wall synthesis in Mycobacterium tuberculosis (Mtb). Isoniazid (INH) is an important first-line drug, which inhibits InhA. The rapid increase in resistance to INH and currently marketed drugs as well as emergence of MDR-TB and XDR-TB has complicated the diagnosis and treatment of Mtb with ever increasing threat to human kind. Herein, we report novel N-methyl carbazole derivatives as potential anti-TB compounds acting directly via InhA inhibition. All the synthesized final compounds were screened against Mtb virulent cell line H37Rv and investigated the InhA enzyme inhibition. Interestingly, compound 9e displayed promising inhibition (91%) at 50 µM concentration and IC50 of 2.82 µM against InhA. To understand the ligand receptor interaction between compound 9e and InhA, molecular docking and molecular dynamics experiments were performed. The computational results were in agreement with the observed experimental data. Further, the cytotoxicity studies on mammalian cells revealed that all the compounds were safe.

Stability studies of pure and mixture form of curcuminoids by reverse phase-HPLC method under various experimental stress conditions.

Since time immemorial, turmeric has been widely marketed and consumed as dietary supplement due to its diverse medicinal properties. Curcuminoids-comprising a mixture of curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC)-are the prime bioactive constituents of turmeric. However, the usage of curcuminoids is limited by their chemical instability. The lack of information on comparative stability profiles of curcuminoids (in pure and mixture form) prompted us to study how pure curcuminoids and their mixtures behave under different stress degradation conditions. The order of stability of curcuminoids when exposed to acidic, alkaline, and oxidative degradation was found to be as follows: BDMC > DMC > CUR. While the pure and mixture forms of curcuminoids were stable against heat, they completely degraded upon exposure to sunlight. The degradation extent of curcuminoids (in mixture form) was substantially less as compared to their pure form; therefore, this suggested the synergistic stabilizing influence of DMC and BDMC in the curcuminoids' mixture.

Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents.

Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 µM; IC50 = 0.48 µM) along with bactericidal (MBC = 12 µM) and intracellular antimycobacterial activities (IC50 = <0.098 µM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 µM) and normal oxygen (MIC = 0.28 µM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 µM for INH-R1; 1.5 µM for INH-R2) and rifampicin (MIC = 2.2 µM for RIF-R1; 6.3 µM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.

An appraisal on recent medicinal perspective of curcumin degradant: Dehydrozingerone (DZG).

Natural products serve as a key source for the design, discovery and development of potentially novel drug like candidates for life threatening diseases. Curcumin is one such medicinally important molecule reported for an array of biological activities. However, it has major drawbacks of very poor bioavailability and solubility. Alternatively, structural analogs and degradants of curcumin have been investigated, which have emerged as promising scaffolds with diverse biological activities. Dehydrozingerone (DZG) also known as feruloylmethane, is one such recognized degradant which is a half structural analog of curcumin. It exists as a natural phenolic compound obtained from rhizomes of Zingiber officinale, which has attracted much attention of medicinal chemists. DZG is known to have a broad range of biological activities like antioxidant, anticancer, anti-inflammatory, anti-depressant, anti-malarial, antifungal, anti-platelet and many others. DZG has also been studied in resolving issues pertaining to curcumin since it shares many structural similarities with curcumin. Considering this, in the present review we have put forward an effort to revise and systematically discuss the research involving DZG with its biological diversity. From literature, it is quite clear that DZG and its structural analogs have exhibited significant potential in facilitating design and development of novel medicinally active lead compounds with improved metabolic and pharmacokinetic profiles.

Novel series of coumarinyl substituted-thiazolidin-2,4-dione analogs as anticancer agents: design, synthesis, spectral studies and cytotoxicity evaluation.

In this research work, a series of eighteen novel coumarinyl substituted thiazolidin-2,4-dione analogs (4a-4r) have been designed by molecular hybridization approach, synthesized and their structures were established on the basis of FTIR, 1H NMR, 13C NMR and elemental (CHN) analysis. These title compounds were screened for their cytotoxicity using MTT assay methodology against five different mammalian cancer cell lines viz. hormone dependant breast adenocarcinoma (MCF7), cervical carcinoma (HeLa), colorectal carcinoma (HT29), lung cancer (A549) and prostate adeno carcinoma (PC3). The cytotoxicity screening studies revealed that MCF-7, HeLa and A549 cancer cell lines were sensitive to all the tested compounds. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most significant effect was observed for compounds 4i (1.06, 2.4 and 3.06 µM) and 4o (0.95, 3.2 and 2.38 µM) against MCF7, HeLa and A549 cell lines respectively. In conclusion, the anticancer results of these promising leads strongly encouraged us for additional lead optimization with the aim of developing more potential anticancer agents.

Novel imidazo[2,1-b]-1,3,4-thiadiazoles as promising antifungal agents against clinical isolate of Cryptococcus neoformans.

We herein report the synthesis and in vitro antimicrobial evaluation of twenty five novel hybrid derivatives of imidazo [2,1-b]-1,3,4-thiadiazole containing chalcones (5a-o) and Schiff bases (6a-j) against three fungal strains (Candida albicans, Cryptococcus neoformans and Aspergillus niger). Most of the tested compounds displayed substantial anti-fungal activity with MICs ranging between 1.56 and 100 µg/mL. Compounds 5a, 5b and 5n exhibited promising activity against C. neoformans at a MIC 1.56 µg/mL. In addition, compound 5n also demonstrated significant antifungal activity against the clinical isolates of C. neoformans at MIC 3.125 µg/mL. However, moderate activity was observed for these compounds against four bacterial strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) and Mycobacterium tuberculosis (H37Rv).

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors from the natural origin: a recent perspective.

Overexpression of epidermal growth factor receptor (EGFR) is seen in a number of human tumors like prostate, colon, breast and ovarian. Their expression is correlated with vascularity and often difficult to diagnose. Though a number of active inhibitors and anticancer drugs against EGFR-tyrosine kinase are known, increase in resistance together with many side effects designate the need for new and improved treatments. Natural products and their analoges have significant contribution in the cancer drug discovery and development process. Therefore in the current review we mainly discuss design, synthesis and structural activity relationship of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors from the natural origin.

An insight into purine, tyrosine and tryptophan derived marine antineoplastic alkaloids.

There is an ever-increasing need for the development of new drugs with safe and improved profile for the treatment of cancer. From time immemorial, nature has been considered as an abundant source of medicinal compounds having therapeutic properties. An enormous chemical diversity is present in thousands and millions of species of microorganisms, marine organisms, plants and animals that can act as potential therapeutic agents against various types of human cancer. Literature survey revealed that many alkaloids isolated from marine cyanobacteria, fungi, algae, sponges and tunicates displayed a wide range of anticancer properties like antiproliferative, antiangiogenic, induction of apoptosis, promoting cytotoxicity by inhibition of topoisomerase activities and tubulin polymerization. In this context, bastadins derived from tyrosine-based alkaloids have been reported as one the important class of anticancer agents. In particular bastadin 6 (24), seems to be a promising natural lead compound for the development of marine natural product-based anticancer therapeutic agents. This review mainly highlights the pharmacologically active scaffolds like purine, tyrosine and tryptophan containing marine alkaloids that exhibit biological activity, including anti-angiogenesis, cytotoxicity and anticancer activity.

Current perspective of natural alkaloid carbazole and its derivatives as antitumor agents.

Throughout our evolution, the importance of natural products for medicine and health has been increasing and it continues to be a key source of novel anticancer drugs, leads and new chemical entities. Among natural products, tricyclic heteroaromatic alkaloids such as carbazoles are an important class of natural and semi-synthetic organic compounds. In the last few decades medicinal role of natural and semi-synthetic carbazoles has expanded significantly, especially as a vital heterocyclic class of antitumor agents. Some of the carbazoles that displayed potential anticancer activity have undergone clinical trials. However, complications arising due to multidrug resistance in clinical trials led to very few of the selected carbazoles being approved for cancer therapy. Planar, polycyclic and aromatic carbazoles exhibit anticancer activity via DNA intercalation. Further many carbazoles can be cytotoxic by inhibiting DNA-dependent enzymes such as telomerase and topoisomerase I/II.

Synthesis of Novel Hybrids Inspired from Bromopyrrole Alkaloids Inhibiting MMP-2 and -12 as Antineoplastic Agents.

Synthesis of novel set of forty semicarbazide/thiosemicarbazide hybrids inspired from marine bromopyrrole alkaloids is reported. Biological screening of these hybrids against a panel of five human cancer cell lines identified a number of hits endowed with interesting cytotoxicity profile. Compounds 5c and 5e (IC50  = 0.03 µm), 5t (IC50  = 0.03 µm), 4s (IC50  = 0.07 µm), and 5n (IC50  = 0.01 µm) displayed maximum cytotoxicity toward hormone-dependent breast cancer cells MCF7, hepatic cancer cells WRL68, colon cancer cells CaCO2 and mouth and oral cancer cells KB403, respectively. The most active hits were further investigated for their potential to inhibit MMP-2 and MMP-12. Compound 5e showed maximum activity (IC50  = 1.8 µm) toward MMP-2. Further, we preformed anti-invasive assay on the most active compounds, where CaCO2 tumor cell migration was significantly decreased (77.9%) by hybrid 5e. The non-toxicity toward human VERO cells (IC50  = 83.1 to 231.8 µm) indicated the selectivity of most active hits (5c, 5e, 5t and 5n) toward cancer cells.

Design, synthesis and evaluation of small molecule imidazo[2,1-b][1,3,4]thiadiazoles as inhibitors of transforming growth factor-ß type-I receptor kinase (ALK5).

A new series of imidazo[2,1-b][1,3,4]thiadiazoles 5(a-g), 6(a-g), 9(a-i) and 12(a-h) were synthesized as transforming growth factor-ß (TGF-ß) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-ß -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d, 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC50 = 0.0012 µM) and elective inhibition (91%) against the P38αkinase at10 µM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.

Design and synthesis of novel antineoplastic agents inspired from marine bromopyrrole alkaloids.

Azetidin-2-one, a ß -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 µM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development.

Synthesis of novel 4-nitropyrrole-based semicarbazide and thiosemicarbazide hybrids with antimicrobial and anti-tubercular activity.

We report the synthesis and screening of forty novel 4-nitropyrrole-semicarbazide conjugates inspired from the reported bio-potential of bromopyrrole alkaloids and semicarbazide derivatives for antimicrobial activity. Herein, hybrids 5k-5o, 5r, 5s and 5t displayed four-fold increased activity (MIC=0.39 µg/mL) against Escherichia coli compared to standard ciprofloxacin. Eight hybrids, 5k-5o and 5r-5t displayed equal antibacterial activity (MIC=1.56 µg/mL) against Klebsiella pneumonia compared to standard ciprofloxacin. Hybrid, 5k-5o (MIC=0.195 µg/mL) displayed highly potent antibacterial activity against MSSA as compared to standard ciprofloxacin. Eight-fold superior activity was observed for four hybrids 5k-5m and 5o (MIC=0.39 µg/mL) against MRSA. Further, nine hybrids displayed four-fold superior antifungal activity (MIC=0.78 µg/mL) compared to standard Amphotericin B. Encouraging MICs of these hybrids recognize them as promising leads for development of potential antimicrobial drugs.