Development of New Drugs to Treat Tuberculosis Based on the Dinitrobenzamide Scaffold.

Tuberculosis (TB) continues to be a major global health challenge and a leading cause of death from infectious diseases. Inspired by the results from a previous work by our group on antimycobacterial N-alkylnitrobenzamides, which are structurally related to the nitrobenzamide family of decaprenylphosphoryl-ß-d-ribose oxidase (DprE1) inhibitors, the present study explored a broad array of substituted benzamides. We particularly focused on previously unexplored 3,5-dinitrobenzamide derivatives. Starting with 3,5-dinitrobenzoic acid, we synthesized a diverse library of amides, incorporating both linear and cyclic amine moieties and also assessed the impact of terminal aromatic groups connected through ether, ester, or amide bonds on the bioactivity of the compounds. The synthesis primarily utilized nucleophilic addition/elimination, SN2, and Mitsunobu reactions. The activity was impacted mainly by two structural features, the addition of an aromatic moiety as a terminal group and the type of linker. The most interesting compounds (c2, d1, and d2, MIC = 0.031 µg/mL) exhibited activities against Mycobacterium Tuberculosis (Mtb) H37Rv comparable to isoniazid. Complementary computational studies helped elucidate potential interactions with DprE1, enhancing our understanding of the molecular basis of their action. Our findings suggest that the most active compounds provide a promising foundation for the continued development of new antimycobacterial agents.

Synthesis, Activity, Toxicity, and In Silico Studies of New Antimycobacterial N-Alkyl Nitrobenzamides.

Tuberculosis (TB) is a disease that plagues the frailest members of society. We have developed a family of N-alkyl nitrobenzamides that exhibit promising antitubercular activities and can be considered a structural simplification of known inhibitors of decaprenylphosphoryl-ß-D-ribofuranose 2'-oxidase (DprE1), an essential Mycobacterium tuberculosis (Mtb) enzyme and an emergent antitubercular target. Hereby, we report the development of these compounds via a simple synthetic methodology as well as their stability, cytotoxicity, and antitubercular activity. Studying their in vitro activity revealed that the 3,5-dinitro and the 3-nitro-5-trifluoromethyl derivatives were the most active, and within these, the derivatives with intermediate lipophilicities presented the best activities (MIC of 16 ng/mL). Additionally, in an ex vivo macrophage model of infection, the derivatives with chain lengths of six and twelve carbon atoms presented the best results, exhibiting activity profiles comparable to isoniazid. Although the proof is not definite, the assessment of susceptibility over multiple mycobacterial species, together with the structure similarities with known inhibitors of this enzyme, support DprE1 as a likely target of action for the compounds. This idea is also reinforced by the docking studies, where the fit of our more active compounds to the DprE1 binding pocket is very similar to what was observed for known inhibitors like DNB1.

Nitrobenzoates and Nitrothiobenzoates with Activity against M. tuberculosis.

Esters of weak acids have shown improved antimycobacterial activity over the corresponding free acids and nitro benzoates in particular have previously shown to have a very intriguing activity. To expand the potential of nitro-derivatives of benzoic acid as antimycobacterial drugs and explore the effects of various structural features on the activity of these compounds, we have obtained a library of 64 derivatives containing esters and thioesters of benzoates and studied their activity against M. tuberculosis, the stability of the compounds, their activation by mycobacterial enzymes and the potential cytotoxicity against human monocytic THP-1 cell line. Our results showed that the most active compounds are those with an aromatic nitro substitution, with the 3,5-dinitro esters series being the most active. Also, the greater antitubercular activity for the nitro derivatives was shown to be unrelated to their pKa values or hydrolysis rates. Given the conventional relationship between nitro-containing substances and toxicity, one might anticipate that the great antimicrobial activity of nitro compounds would be associated with high toxicity; yet, we have not found such a relationship. The nitrobenzoate scaffold, particularly the 3,5-dinitrobenzoate scaffold, merits further investigation, because it has the potential to generate future antimycobacterial agents with improved activity.

Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis.

One interesting approach to fight tuberculosis is the use of prodrugs that often have shown improved biological activities over drugs with poor absorption or difficulty to cross membranes. Previous studies demonstrate that weak acids such as benzoic acid, present antimycobacterial activity. Moreover, esters of those acids revealed to be a viable alternative since they may diffuse more easily through the cell membranes. Previously we showed that mycobacteria can easily activate benzoic acid esters by conversion to the corresponding acid. Since Zhang postulated that the activity of the acids can be dependent on their pKa, we set up to synthesize a library of benzoates with different electron withdrawing groups (4-chloro, 2,6-dichloro, 3,5-dichloro, 4-nitro, and 3,5 dinitro), to modulate pKa of the liberated acid and different alkoxy substituents (propyl, hexyl, and phenyl) to modulate their lipophilicity, and tested the activity of the esters and the corresponding free acids against mycobacteria. We also studied the activation of the esters by mycobacterial enzymes and the stability of the compounds in buffer and plasma. We concluded that all the benzoates in our study can be activated by mycobacterial enzymes and that the phenyl and hexyl esters presented higher activity than the corresponding free acids, with the nitrobenzoates, and especially the dinitrobenzoates, showing very interesting antitubercular activity that deserve further exploration. Our results did not show a correlation between the activity and the pKa of the acids.

Muscular Dystrophy and Heart Failure: An Unusual Association.

Type one muscular dystrophy (DM1) is the most common inherited muscular dystrophy in the adult population. Typically, DM1 presents as myotonia, muscle weakness, cataracts, and cardiac abnormalities, mainly in the conduction system. Although left ventricular dysfunction is not the most common manifestation of DM1, it can be seen with disease progression. The presentation of DM1 as a de novo heart failure is unusual, making its diagnosis a clinical challenge.

Right-Side Endocarditis: A Typical Presentation in an Atypical Patient.

Right-side endocarditis (RSE) is a well-defined clinical entity, rarer than left-side endocarditis. Known risk factors include intravenous drug use or the presence of medical devices. The most frequently affected valve is the tricuspid valve. In most cases, medical treatment is enough. Surgical treatment is reserved for failed medical therapy or in the presence of large vegetations. Although there is a high recurrence rate in intravenous drug users (IDU), RSE has a generally good prognosis. We present the case of a 70-year-old male with no known previous diseases other than alcohol abuse. He was admitted with fever, cough, hemoptysis and a weight loss of 8 kg in two months. Chest X-ray revealed two images of condensation, one in the right pulmonary base and another in the superior right lobe. A computerized tomography of the thorax revealed a subsegmental pulmonary embolism. The patient refused hospitalization and was discharged medicated with levofloxacin and apixaban. In ambulatory, there was a decrease in size of the lesions but with a new lesion in the right hemithorax. Two months after the first episode, the patient is admitted with the same symptoms. The transthoracic echocardiogram showed a 20cm vegetation in the tricuspid valve. He was admitted to the hospital and received treatment with penicillin and gentamicin after isolation of Streptococcus mitis in the blood cultures. Surgical treatment was needed after a weak response to antibiotics, with a good evolution.

Drug-Induced Liver Injury Induced by Bioflavonoids.

Drug-induced liver injury (DILI) is a relatively rare disease with a vast spectre of clinical manifestations. Its diagnosis is based on the exclusion of other causes of liver disease. The identification of a causal agent is based on the temporal relation between the symptoms and their resolution after stopping the suspected drug. Many drugs have been described as causative agents of DILI; however, bioflavonoids have never been implied with an idiosyncratic DILI in the literature.

Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes.

Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials.