A consensus reverse docking approach for identification of a competitive inhibitor of acetyltransferase enhanced intracellular survival protein from Mycobacterium tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary.

Effects of tafenoquine against active, dormant and resistant Mycobacterium tuberculosis.

Antimalarial drugs have been suggested as promising scaffolds with anti-tubercular activities. In this work, we demonstrated, for the first time, the effectiveness of tafenoquine against mycobacteria. Firstly, tafenoquine inhibited the growth of Mycobacterium smegmatis and Mycobacterium tuberculosis with lower MICs values as compared to other antimalarial drugs, such as mefloquine, chloroquine, and primaquine.

Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts.

Human thymidine phosphorylase (hTP) is overexpressed in several solid tumors and is commonly associated with aggressiveness and unfavorable prognosis. 6-(((1,3-Dihydroxypropan-2-yl)amino)methyl)-5-iodopyrimidine-2,4(1H,3H)-dione (CPBMF-223) is a noncompetitive hTP inhibitor, which has been described as a tumor angiogenesis inhibitor. The present study investigated the effects of CPBMF-223 in a xenograft tumor induced by human colorectal carcinoma cells (HCT-116).

Nonclinical evaluation of IQG-607, an anti-tuberculosis candidate with potential use in combination drug therapy.

New effective compounds to treat tuberculosis are urgently needed. IQG-607 is an orally active anti-tuberculosis drug candidate, with promising preliminary safety profile and anti-mycobacterial activity in both in vitro and in vivo models of tuberculosis infection. Here, we evaluated the mutagenic and genotoxic effects of IQG-607, and its interactions with CYP450 isoforms.

Design of Novel Inhibitors of Human Thymidine Phosphorylase: Synthesis, Enzyme Inhibition, in Vitro Toxicity, and Impact on Human Glioblastoma Cancer.

Overexpressed human thymidine phosphorylase (hTP) has been associated with cancer aggressiveness and poor prognosis by triggering proangiogenic and antiapoptotic signaling. Designed as transition-state analogues by mimicking the oxacarbenium ion, novel pyrimidine-2,4-diones were synthesized and evaluated as inhibitors of hTP activity. The most potent compound (8g) inhibited hTP in the submicromolar range with a noncompetitive inhibition mode with both thymidine and inorganic phosphate substrates.

Pre-clinical evaluation of quinoxaline-derived chalcones in tuberculosis.

New effective compounds for tuberculosis treatment are needed. This study evaluated the effects of a series of quinoxaline-derived chalcones against laboratorial strains and clinical isolates of M. tuberculosis.

Effect of the bradykinin 1 receptor antagonist SSR240612 after oral administration in Mycobacterium tuberculosis-infected mice.

The role, if any, played by the kinin system in tuberculosis infection models, either in vivo or in vitro, was investigated. The effects of Mycobacterium tuberculosis infection on C57BL/6 wild type, BR-/-, BR-/- and double BR/BR knockout mice were evaluated. Immunohistochemistry analysis was carried out to assess BR and BR expression in spleens and lungs of M.

Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis.

M. tuberculosis and parasites of the genus Leishmania present the type II fatty acid biosynthesis system (FASII). The pentacyano(isoniazid)ferrate(II) compound, named IQG-607, inhibits the enzyme 2-trans-enoyl-ACP(CoA) reductase from M.

Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis.

IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the gene. The (S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages.

Construction of Mycobacterium tuberculosis cdd knockout and evaluation of invasion and growth in macrophages.

Cytidine deaminase (MtCDA), encoded by cdd gene (Rv3315c), is the only enzyme identified in nucleotide biosynthesis pathway of Mycobacterium tuberculosis that is able to recycle cytidine and deoxycytidine. An M. tuberculosis knockout strain for cdd gene was obtained by allelic replacement.

Preclinical pharmacokinetic profiling of IQG-607, a potential oral metallodrug to treat tuberculosis.

IQG-607 is an analog of isoniazid with anti-tuberculosis activity. This work describes the development and validation of an HPLC method to quantify pentacyano(isoniazid)ferrate(II) compound (IQG-607) and the pharmacokinetic studies of this compound in mice. The method showed linearity in the 0.

Activity of 2-(quinolin-4-yloxy)acetamides in Mycobacterium tuberculosis clinical isolates and identification of their molecular target by whole-genome sequencing.

The 2-(quinolin-4-yloxy)acetamides (QOAs) have been reported to be promising molecules for tuberculosis treatment. Recent studies demonstrated their potent antimycobacterial activity, biological stability and synergism with rifampicin. The identification of the molecular target is an essential step towards the development of a novel drug candidate.

Toxicological profile of IQG-607 after single and repeated oral administration in minipigs: An essential step towards phase I clinical trial.

IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in vitro and in vivo. Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220 mg/kg) to female and male minipigs did not result in any morbidity or mortality.

Functional, thermodynamics, structural and biological studies of in silico-identified inhibitors of Mycobacterium tuberculosis enoyl-ACP(CoA) reductase enzyme.

Novel chemotherapeutics agents are needed to kill Mycobacterium tuberculosis, the main causative agent of tuberculosis (TB). The M. tuberculosis 2-trans-enoyl-ACP(CoA) reductase enzyme (MtInhA) is the druggable bona fide target of isoniazid.

Preclinical safety evaluation of IQG-607 in rats: Acute and repeated dose toxicity studies.

In the present study, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in rats. Single oral administration of IQG-607 (300 or 2000 mg/kg) on female rats did not result in any mortality. No gross lesions were observed in the animals at necropsy.

Mefloquine and its oxazolidine derivative compound are active against drug-resistant Mycobacterium tuberculosis strains and in a murine model of tuberculosis infection.

Repurposing of drugs to treat tuberculosis (TB) has been considered an alternative to overcome the global TB epidemic, especially to combat drug-resistant forms of the disease. Mefloquine has been reported as a potent drug to kill drug-resistant strains of Mycobacterium tuberculosis. In addition, mefloquine-derived molecules have been synthesised and their effectiveness against mycobacteria has been assessed.

IQG-607 abrogates the synthesis of mycolic acids and displays intracellular activity against Mycobacterium tuberculosis in infected macrophages.

In this work, the antitubercular activity of a pentacyano(isoniazid)ferrate(II) compound (IQG-607) was investigated using a macrophage model of Mycobacterium tuberculosis infection. Importantly, treatment of M.-tuberculosis-infected macrophages with IQG-607 significantly diminished the number of CFU compared with the untreated control group.

Activity of IQG-607, a new orally active compound, in a murine model of Mycobacterium tuberculosis infection.

We have previously demonstrated a potent in vitro inhibitory activity for two pentacyano(isoniazid)ferrate(II) compounds, namely IQG-607 and IQG-639, against the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase enzyme. In this study, the activity of these compounds was evaluated using an in vivo murine model of tuberculosis. Swiss mice were infected with M.