Novel quinoline derivatives with broad-spectrum antiprotozoal activities.

Several quinoline derivatives incorporating arylnitro and aminochalcone moieties were synthesized and evaluated in vitro against a broad panel of trypanosomatid protozoan parasites responsible for sleeping sickness (Trypanosoma brucei rhodesiense), nagana (Trypanosoma brucei brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania infantum). Several of the compounds demonstrated significant antiprotozoal activity. Specifically, compounds 2c, 2d, and 4i displayed submicromolar activity against T. b. rhodesiense with half-maximal effective concentration (EC50) values of 0.68, 0.8, and 0.19 µM, respectively, and with a high selectivity relative to human lung fibroblasts and mouse primary macrophages (∼100-fold). Compounds 2d and 4i also showed considerable activity against T. b. brucei with EC50 values of 1.4 and 0.4 µM, respectively.

Tractable Quinolone Hydrazides Exhibiting Sub-Micromolar and Broad Spectrum Antitrypanosomal Activities.

Nagana and Human African Trypanosomiasis (HAT), caused by (sub)species of Trypanosoma, are diseases that impede human and animal health, and economic growth in Africa. The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed. A series of 20 novel quinolone compounds with affordable synthetic routes was made and evaluated in vitro against Trypanosoma brucei and HEK293 cells. Of the 20 compounds, 12 had sub-micromolar potencies against the parasite (EC50 values=0.051-0.57 µM), and most were non-toxic to HEK293 cells (CC50 values>5 µM). Two of the most potent compounds presented sub-micromolar activities against other trypanosome (sub)species (T. cruzi and T. b. rhodesiense). Although aqueous solubility is poor, both compounds possess good logD values (2-3), and either robust or poor microsomal stability profiles. These varying attributes will be addressed in future reports.

Design and synthesis of imidazo[1,2-a]pyridine-chalcone conjugates as antikinetoplastid agents.

A library of imidazo[1,2-a]pyridine-appended chalcones were synthesized and characterized using 1 H NMR, 13 C NMR and HRMS. The synthesized analogues were screened for their antikinetoplastid activity against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. The analogues were also tested for their cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all screened derivatives, 7f was found to be the most active against T. cruzi and T. b. brucei exhibiting IC50 values of 8.5 and 1.35 µM, respectively. Against T. b. rhodesiense, 7e was found to be the most active with an IC50 value of 1.13 µM. All synthesized active analogues were found to be non-cytotoxic against MRC-5 and PMM with selectivity indices of up to more than 50.

Steroid-triazole conjugates: A brief overview of synthesis and their application as anticancer agents.

Steroids are biomolecules that play pivotal roles in various physiological and drug discovery processes. Abundant research has been fuelled towards steroid-heterocycles conjugates over the last few decades as potential therapeutic agents against various diseases especially as anticancer agents. In this context various steroid-triazole conjugates have been synthesized and studied for their anticancer potential against various cancer cell lines. A thorough search of the literatures revealed that a concise review pertaining the present topic is not compiled. Therefore, in thus review we summarize the synthesis, anticancer activity against various cancer cell lines and structure activity relationship (SAR) of various steroid-triazole conjugates. This review can lay down the path towards the development of various steroid-heterocycles conjugates with lesser side effects and profound efficacy.

Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling.

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a quinolone nucleus. Twenty-two compounds were synthesised and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC90 <0.244 µM. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.

2-Aroyl quinazolinone: Synthesis and in vitro anti-parasitic activity.

Trypanosomes and Leishmania are parasitic protozoans that affect millions of people globally. Herein we report the synthesis of 2-aroyl quinazolinones and their antiprotozoal efficacy against Trypanosoma brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. These compounds were counter-screened against a human cell line for cytotoxicity. Thirteen of the twenty target compounds in this study inhibited the growth of these parasites, with compounds KJ1, and KJ10 exhibiting IC50 values of 4.7 µM (T. b. brucei) and 1.1 µM (T. b. rhodesiense), respectively.

Quinolone-3-amidoalkanol: A New Class of Potent and Broad-Spectrum Antimicrobial Agent.

Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (<1 µg/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of >98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

Exploration of 4-aminopyrrolo[2,3-d]pyrimidine as antitubercular agents.

Tuberculosis (TB) is one of the leading causes of death worldwide. Developing new anti-TB compounds using cost-effective processes is critical to reduce TB incidence and accomplish the End TB Strategy milestone. Herein, we describe the synthesis and structure-activity relationships of a library of thirty 7H-Pyrrolo[2,3-d]pyrimidine derivatives providing insights into the contributions of different aromatic, aryl and alkyl substitution at the C-4 position of the 7-deazapurine ring. The minimum inhibitory concentration (MIC) of the compounds against the green fluorescent protein (GFP) reporter strain of Mycobacterium tuberculosis was assayed using the standard broth microdilution method, and cell toxicity was determined using the MTT assay. Sixteen compounds displayed in vitro activity against the GFP reporter strain of Mycobacterium tuberculosis with MIC90 values of 0.488-62.5 µM. This study highlights the most potent derivative, N-(4-phenoxy phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a MIC90 value of 0.488 µM and was non-cytotoxic to the Vero cell line. Moreover, all the potent compounds from this series have a ClogP value less than 4 and molecular weight < 400; thus, likely to maintain drug-likeness during lead optimisation.

Arylnitro monocarbonyl curcumin analogues: Synthesis and in vitro antitubercular evaluation.

Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties, one of which is antitubercular activity. It demonstrates antitubercular activity by directly inhibiting Mycobacterium tuberculosis (M.tb) and also enhances immune responses that ultimately lead to the elimination of M.tb by macrophages. This natural product is, however, unstable, and several analogues, noticeably monocarbonyl analogues, have been synthesized to overcome this challenge. Curcumin and its monocarbonyl analogues reported so far exhibit moderate antitubercular activity in the range of 7 to 16 µM. Herein, we report a straightforward synthesis of novel monocarbonyl curcumin analogues, their antitubercular activity, and the structure-activity relationship. The hit compound from this study, 3a, exhibits potent MIC90 values in the range of 0.2 to 0.9 µM in both ADC and CAS media.

Quinolone: a versatile therapeutic compound class.

The discovery of nalidixic acid is one pinnacle in medicinal chemistry, which opened a new area of research that has led to the discovery of several life-saving antimicrobial agents (generally referred to as fluoroquinolones) for over decades. Although fluoroquinolones are frequently encountered in the literature, the utility of quinolone compounds extends far beyond the applications of fluoroquinolones. Quinolone-based compounds have been reported for activity against malaria, tuberculosis, fungal and helminth infections, etc. Hence, the quinolone scaffold is of great interest to several researchers in diverse disciplines. This article highlights the versatility of the quinolone pharmacophore as a therapeutic agent beyond the fluoroquinolone profile.

Synthesis and in vitro antiprotozoal evaluation of novel metronidazole-Schiff base hybrids.

Herein we report the synthesis of 21 novel small molecules inspired by metronidazole and Schiff base compounds. The compounds were evaluated against Trichomonas vaginalis and cross-screened against other pathogenic protozoans of clinical relevance. Most of these compounds were potent against T. vaginalis, exhibiting IC50 values < 5 µM. Compound 20, the most active compound against T. vaginalis, exhibited an IC50 value of 3.4 µM. A few compounds also exhibited activity against Plasmodium falciparum and Trypanosomal brucei brucei, with compound 6 exhibiting an IC50 value of 0.7 µM against P. falciparum and compound 22 exhibiting an IC50 value of 1.4 µM against T.b. brucei. Compound 22 is a broad-spectrum antiprotozoal agent, showing activities against all three pathogenic protozoans under investigation.

Nigella sativa L. and Its Active Compound Thymoquinone in the Clinical Management of Diabetes: A Systematic Review.

Despite existing conventional hypoglycemic drugs to manage diabetes, their non-availability and cost in low-income countries coupled with the associated side effects remain a major concern. Consequently, exploring for alternative treatments to manage diabetes has been a continuous priority. Nigella sativa L. (NS) (Family: Ranunculaceae) is regarded as a valuable traditional remedy in diabetes management and extensively studied for its biological properties. This systematic review provides a comprehensive and critical analysis of clinical studies on the efficacy, safety, and mechanism of action of NS and its compound thymoquinone (TQ) in diabetes management. The main scientific databases which were scrutinised were Scopus, PubMed, Google Scholar, and Web of Science. Data search was conducted from inception to January 2022. A total of 17 clinical studies were obtained; 16 studies on Nigella sativa L. and 1 study on its compound TQ. N. sativa was found to be highly potent in terms of its hypoglycemic activity when compared to placebo based on improvement in parameters including fasting blood glucose (FBG), postprandial blood glucose (PPBG), Hemoglobin A1C (HbA1c), homeostatic model assessment for insulin resistance (HOMA-IR), and homeostatic model assessment for assessment of beta-cell functionality (HOMA-ß). The compound TQ in combination with a daily dose of metformin demonstrated a greater reduction in the levels of HbA1c and blood glucose compared to metformin alone. The bioavailability of TQ can be enhanced by using nanoparticulate drug delivery systems. Considering the findings of the clinical studies along with negligible adverse effects, NS has strong potential application in bioproduct development for the management of diabetes. Further investigations should explore the detailed mechanism of actions by which TQ exerts its therapeutic antidiabetic effects to provide more insights into its clinical use in the management of diabetes.

Nitrothiazole-Thiazolidinone Hybrids: Synthesis and in Vitro Antimicrobial Evaluation.

Herein we report the synthesis of novel compounds inspired by the antimicrobial activities of nitroazole and thiazolidin-4-one based compounds reported in the literature. Target compounds were investigated in vitro for antitubercular, antibacterial, antifungal, and overt cell toxicity properties. All compounds exhibited potent antitubercular activity. Most compounds exhibited low micromolar activity against S. aureus and C. albicans with no overt cell toxicity against HEK-293 cells nor haemolysis against human red blood cells. Notably, compound 3b exhibited low to sub-micromolar activities against Mtb, MRSA, and C. albicans. 3b showed superior activity (0.25 µg/ml) against MRSA compared to vancomycin (1 µg/ml).

Investigation of quinolone-tethered aminoguanidine as novel antibacterial agents.

A recent study identified quinolone-based thiosemicarbazone with an MIC90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC90 values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating >50% growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non-pan-assay interfering compound.

Design, synthesis and evaluation of amino-3,5-dicyanopyridines and thieno[2,3-b]pyridines as ligands of adenosine A1 receptors for the potential treatment of epilepsy.

Due to the implication of adenosine in seizure suppression, adenosine-based therapies such as adenosine receptor (AR) agonists have been investigated. This study aimed at investigating thieno[2,3-b]pyridine derivatives as non-nucleoside A1 agonists that could be used in pharmaco-resistant epilepsy (PRE). Compound 7c (thieno[2,3-b]pyridine derivative), displayed good binding affinity to the rA1 AR (K i = 61.9 nM). This could be a breakthrough for further investigation of this heterocyclic scaffold as potential ligand. In silico evaluation of this compound raised bioavailability concerns but performed well on drug-likeness tests. The effect of intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines from the lead compounds, amino-3,5-dicyanopyridine derivatives (6a-s) in relation to AR binding was also evaluated. A significant loss of activity against rA1/rA2A ARs with cyclisation was revealed. Amino-3,5-dicyanopyridines exhibited greater affinity towards rA1 ARs (K i < 10 nM) than rA2A. Compound 6c had the best rA1 affinity (K i = 0.076 nM). Novel compounds (6d, 6k, 6l, 6m, 6n, 6o, 6p) were highly selective towards rA1 AR (K i between 0.179 and 21.0 nM). Based on their high selectivity for A1 ARs, amino-3,5-dicyanopyridines may be investigated further as AR ligands in PRE with the right structural optimisations and formulations. A decrease in rA1 AR affinity is observed with intramolecular cyclisation that occurs during synthesis of thieno[2,3-b]pyridines (7a, 7d, 7c) from amino-3,5-dicyanopyridine derivatives (6a, 6f, 6g).

The evaluation of N-propargylamine-2-aminotetralin as an inhibitor of monoamine oxidase.

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC50 = 0.721 µM) compared to MAO-B (IC50 = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression.

New fused pyrroles with rA1/A2A antagonistic activity as potential therapeutics for neurodegenerative disorders.

In a pilot study, eleven pyrrolopyridine and pyrrolopyrimidine derivatives (specifically, 7-azaindole and 7-deazapurine derivatives) were synthesised by Suzuki cross-coupling reactions and evaluated via radioligand binding assays as potential adenosine receptor (AR) antagonists in order to further investigate the structure-activity relationships of these compounds. 6-Chloro-4-phenyl-1H-pyrrolo[2,3-b]pyridine, with a 7-azaindole scaffold, was identified as a selective A1 AR antagonist with a rA1Ki value of 0.16 µM, and interestingly, the addition of a N-atom to the aforementioned fused heterocyclic ring system, creating corresponding 7-deazapurines, led to a dual A1/A2A AR ligand (2-chloro-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine: rA1Ki: 0.19 ± 0.02 µM; rA2AKi: 0.43 ± 0.01 µM). Introducing an additional N-atom into the heterocyclic ring system was tolerable for rA1 AR affinity and also led to rA2A AR affinity. This pilot study concluded that new 7-azaindole and 7-deazapurine derivatives represent interesting scaffolds for design of A1 and/or A2A AR antagonists.

Exploration of chalcones and related heterocycle compounds as ligands of adenosine receptors: therapeutics development.

Adenosine receptors (ARs) are ubiquitously distributed throughout the mammalian body where they are involved in an extensive list of physiological and pathological processes that scientists have only begun to decipher. Resultantly, AR agonists and antagonists have been the focus of multiple drug design and development programmes within the past few decades. Considered to be a privileged scaffold in medicinal chemistry, the chalcone framework has attracted a substantial amount of interest in this regard. Due to the potential liabilities associated with its structure, however, it has become necessary to explore other potentially promising compounds, such as heterocycles, which have successfully been obtained from chalcone precursors in the past. This review aims to summarise the emerging therapeutic importance of adenosine receptors and their ligands, especially in the central nervous system (CNS), while highlighting chalcone and heterocyclic derivatives as promising AR ligand lead compounds.

Validating a sensitive LCMS method for the quantitation of artemisinin in Artemisia spp. including material used in retracted clinical trials.

Two recent clinical trials reported that Artemisia afra contained significant amounts of the bioactive compound artemisinin. We suspected sample contamination and therefore obtained the A. afra material for testing. A sensitive liquid chromatography mass spectrometry method was developed and validated for the accurate quantitation of artemisinin in Artemisia annua and A. afra plant material. This validated analytical method, with a limit of detection of 0.22 ng/mL (0.22 pg on column), which is an order of magnitude more sensitive than recently published methods, was applied to quantify artemisinin in a collection of Artemisia samples including the A. afra material that was used in the clinical trials.All 16A. annua samples (oldest sample 21 years old) contained the expected levels of artemisinin (0.12-0.63%) whilst none of the A. afra samples in our collection contained any trace of artemisinin (> 0.00001%). However, the A. afra samples used in the clinical trials did contain detectable amounts of artemisinin (0.0013% and 0.0011% vs the claimed amount of 0.0045%).The authors of the clinical trials suspected that cross contamination during sample handling and preparation was likely, reconfirming the importance of having analytical quality control methods in place before clinical trials are conducted. Quality control and ensuring safety of trial participants is of utmost importance.