Expanding the chemical space of ester of quinoxaline-7-carboxylate 1,4-di--oxide derivatives as potential antitubercular agents.

Tuberculosis is a worldwide health problem that warrants attention given that the current treatment options require a long-term chemotherapeutic period and have reported the development of () multidrug resistant strains. In this study, -butyl and isobutyl quinoxaline-7-carboxylate 1,4-di--oxide were evaluated against replicating and non-replicating H37Rv strains. The results showed that seventeen of the twenty-eight derivatives have minimum inhibitory concentration (MIC) values lower than isoniazid (2.

Isolation and Characterization of Anti-Mycobacterial Natural Products from a sp. Marine Sponge.

Tuberculosis (TB) is a dreadful infectious disease and a leading cause of mortality and morbidity worldwide, second in 2020 only to severe acute respiratory syndrome 2 (SARS-Cov-2). With limited therapeutic options available and a rise in multidrug-resistant tuberculosis cases, it is critical to develop antibiotic drugs that display novel mechanisms of action. Bioactivity-guided fractionation employing an Alamar blue assay for strain H37Rv led to the isolation of duryne () from a marine sponge sp.

Insights into the Chemical Diversity of Selected Fungi from the Tza Itzá Cenote of the Yucatan Peninsula.

Cenotes are habitats with unique physical, chemical, and biological features. Unexplored microorganisms from these sinkholes represent a potential source of bioactive molecules. Thus, a series of cultivable fungi ( spp.

New Terpenoids from the Corticioid Fungus Punctularia atropurpurascens and their Antimycobacterial Evaluation.

Chemical investigation of strain HM1 (Punctulariaceae), a corticioid isolated from a decorticated piece of bark collected in Bosque de Tlalpan, Mexico City, led to the isolation of a new drimane, 1--hydroxy-isodrimenine (1: ) and a new tetrahydroxy kauranol, 16-hydroxy-phlebia--kauranol (2: ), together with the known -phenylacetamide (3: ). Structures of all compounds were elucidated by spectroscopic and spectrometric methods, and the absolute configuration of 1: and 2: was confirmed via single-crystal X-ray crystallography. The isolated compounds showed modest antimycobacterial activity.

Chemical Diversity and Antimicrobial Potential of Cultivable Fungi from Deep-Sea Sediments of the Gulf of Mexico.

A collection of 29 cultivable fungal strains isolated from deep-sea sediments of the Gulf of Mexico were cultivated under the "one strain, many compounds" approach to explore their chemical diversity and antimicrobial potential. From the 87 extracts tested, over 50% showed antimicrobial activity, and the most active ones were those from cultures grown at 4 °C in darkness for 60 days (resembling deep-sea temperature). PCA analysis of the LC-MS data of all the extracts confirmed that culture temperature is the primary factor in the variation of the 4462 metabolite features, accounting for 21.

Novel Linker Variants of Antileishmanial/Antitubercular 7-Substituted 2-Nitroimidazooxazines Offer Enhanced Solubility.

Antitubercular 7-substituted 2-nitroimidazo[2,1-][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated and but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold.

Identification of benzothiazinones containing an oxime functional moiety as new anti-tuberculosis agents.

A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.

Strategies in anti-Mycobacterium tuberculosis drug discovery based on phenotypic screening.

The rise of multi- and extensively drug-resistant Mycobacterium tuberculosis (M. tb) strains and co-infection with human immunodeficiency virus has escalated the need for new anti-M. tb drugs.

Identification of Pyrazolo[1,5-]pyridine-3-carboxamide Diaryl Derivatives as Drug Resistant Antituberculosis Agents.

A series of pyrazolo[1,5-]pyridine-3-carboxamide (PPA) derivatives bearing diaryl side chain was designed and synthesized as new antituberculosis agents, aiming to improve the efficacy toward drug resistant () strains. Most of the substituted diphenyl and heterodiaryl PPAs exhibited excellent potency against the drug susceptive H37Rv strain (MIC < 0.002-0.

Synthesis and antimicrobial activities of N-hydroxyagelasine analogs and revision of the structure of ageloximes.

(+)-N-Hydroxyagelasine D, the enantiomer of the proposed structure of (-)-ageloxime D, as well as N-hydroxyagelasine analogs were synthesized by selective N-7 alkylation of N-[tert-butyl(dimethyl)silyloxy]-9-methyl-9H-purin-6-amine in order to install the terpenoid side chain, followed by fluoride mediated removal of the TBDMS-protecting group. N-Hydroxyagelasine D and the analog carrying a geranylgeranyl side chain displayed profound antimicrobial activities against several pathogenic bacteria and protozoa and inhibited bacterial biofilm formation. However these compounds were also toxic towards mammalian fibroblast cells (MRC-5).

Anti- Activity of Esters of Quinoxaline 1,4-Di--Oxide.

Tuberculosis continues to be a public health problem in the world, and drug resistance has been a major obstacle in its treatment. Quinoxaline 1,4-di--oxide has been proposed as a scaffold to design new drugs to combat this disease. To examine the efficacy of this compound, this study evaluates methyl, ethyl, isopropyl, and n-propyl esters of quinoxaline 1,4-di--oxide derivatives in vitro against (pansusceptible and monoresistant strains).

Synthesis and Activity against of Olivacine and Oxygenated Derivatives.

The tetracyclic pyrido[4,3-]carbazole olivacine and four of its oxygenated derivatives have been synthesized by a late-stage palladium-catalyzed Heck-type cyclization of the pyrrole ring as a key step. In a test for the inhibition of the growth of , 9-methoxyolivacine showed the most significant inhibitory activity against with an MIC value of 1.5 μM.

Pyrazole and imidazo[1,2-b]pyrazole Derivatives as New Potential Antituberculosis Agents.

Background: We screened a large library of differently decorated imidazo-pyrazole and pyrazole derivatives as possible new antitubercular agents and this preliminary screening showed that many compounds are able to totally inhibit Mycobacterium growth (>90 %). Among the most active compounds, we selected some new possible hits based on their similarities and, at the same time, on their novelty with respect to the pipeline drugs.

Methods: In order to increase the potency and obtain more information about structure-activity relationship (SAR), we designed and synthesized three new series of compounds (2a-e, 3a-e, and 4a-l).

Development of (6 R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5 H-imidazo[2,1- b][1,3]oxazine (DNDI-8219): A New Lead for Visceral Leishmaniasis.

Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive.

Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid.

A published study of structural features associated with the aerobic and anaerobic activities of 4- and 5-nitroimidazoles had found that the 3-nitro isomer of pretomanid, , displayed interesting potencies, including against nitroreductase mutant . However, recent nuclear magnetic resonance analyses of two trace byproducts, isolated from early process optimization studies toward a large-scale synthesis of pretomanid, raised structural assignment queries, particularly for , stimulating further investigation. Following our discovery that the reported compound was a 6-nitroimidazooxazole derivative, we developed a synthesis of authentic via nitration of the chiral des-nitro imidazooxazine alcohol in trifluoroacetic or acetic anhydride, and verified its identity through an X-ray crystal structure.

Discovery of new leads against Mycobacterium tuberculosis using scaffold hopping and shape based similarity.

BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile.

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]thiazoles: Facile synthesis and comparative appraisal against tuberculosis and neglected tropical diseases.

As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis.

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis.

Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity.

Benzylsulfanyl benzo-heterocycle amides and hydrazones as new agents against drug-susceptible and resistant .

A series of benzylsulfanyl benzo-heterocycle amides and hydrazones were synthesized and evaluated for anti-tubercular activities. The isonicotinyl hydrazone derivatives , and exhibited good anti-tubercular activity against HRv (ATCC #27294) with MIC values of 0.23, 0.

Anti-tuberculosis activity and structure-activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives.

A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC values ranging from 1.

Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea.

Tuberculosis is a major threat for mankind and the emergence of resistance strain of Mycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for human civilization. In this study, we have synthesized different diaryl urea derivatives targeting the inhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46, 57, 58 and 86 showed MIC values ≤ 10 μg/ml against H37Rv and mc6030 strains.

Pyrazolo[1,5-a]pyridine-3-carboxamide hybrids: Design, synthesis and evaluation of anti-tubercular activity.

A series of pyrazolo[1,5-a]pyridine-3-carboxamide hybrids were designed and evaluated as novel anti-tubercular agents. The representative hybrid 7 exhibited promising in vitro activity against susceptive strain H37Rv and a panel of drug-resistant Mtb strains with MIC values of 0.006 μg/mL and ranged from 0.

Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase.

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB.

Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis.

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL.