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TB, caused by Mycobacterium tuberculosis , is one of the deadliest infections worldwide. The co-infection with HIV and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains have further increased the burden for this disease. In the attempt to respond to the constant need of novel therapeutic options, we herein report the discovery of 2,4-diphenyl-1 H -imidazoles as effective antitubercular agents, with MIC in the low micromolar range against actively replicating and persistent M. tuberculosis strains. The good activity, along with the lack of toxicity and the feasible synthesis, underscore their value as novel scaffolds for the development of new anti-TB drugs. [ABSTRACT FROM AUTHOR]

Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysine-specific demethylase 1 (LSD1 or KDM1A) is highly expressed in different cancer types and inhibiting KDM1A activity seems to have high therapeutic potential in cancer treatment. In the recent years, several inhibitors of KDM1A have been prepared and disclosed. The majority of these derivatives were designed based on the structure of tranylcypromine, as the cyclopropane core is responsible for the covalent interaction between the inhibitor and the catalytic domain of KDM proteins. In this study, we have further extended the SAR regarding compounds 1a – e , which were recently found to inhibit KDM1A with good activity. The decoration of the phenyl ring at the β-position of the cyclopropane ring with small functional groups, mostly halogenated, and in particular at the meta position, led to a significant improvement of the inhibitory activity against KDM1A, as exemplified by compound 44a , which has a potency in the low nanomolar range (31 nM). [ABSTRACT FROM AUTHOR]

Abstract: Tuberculosis (TB) is one of the deadliest infectious diseases of all times, and its recent resurgence is a supreme matter of concern. Co-infection with HIV and, in particular, the continuous isolation of new resistant strains, makes the discovery of novel anti-TB agents a strategic priority. The research of novel agents should be driven by the accessibility of the synthetic procedure and, in particular, by the lack of cross-resistance with the drugs already marketed. Moreover, in order to shorten the duration of the therapy, and therefore decrease the rate of resistance, these molecules should be active also against the nonreplicating persistent form (NRP-TB) of the infection. The availability of an in-house small library of compounds prompted us to investigate their anti-TB activity. Two compounds, embodying a 2-aminothiazole scaffold, were found to possess a certain inhibitory activity toward Mycobacterium tuberculosis H37Rv, and therefore a medicinal chemistry campaign was initiated in order to increase the activity of the hit compounds and, especially, construct a plausible body of structure–activity relationships. The potency of the hit compound was successfully improved, and, much more importantly, some of the molecules synthesized were found to be active toward the persistent phenotype, and, also, toward a panel of resistant strains. These findings encourage further investigations around this interesting antitubercular chemotype. [Copyright &y& Elsevier]

Indoleamine 2,3-dioxygenases (IDOs) degrade l -tryptophan to kynurenines and drive the de novo synthesis of nicotinamide adenine dinucleotide. Unsurprisingly, various invertebrates, vertebrates, and even fungi produce IDO. In mammals, IDO1 also serves as a homeostatic regulator, modulating immune response to infection via local tryptophan deprivation, active catabolite production, and non-enzymatic cell signaling. Whether fungal Idos have pleiotropic functions that impact on host-fungal physiology is unclear. Here, we show that Aspergillus fumigatus possesses three ido genes that are expressed under conditions of hypoxia or tryptophan abundance. Loss of these genes results in increased fungal pathogenicity and inflammation in a mouse model of aspergillosis, driven by an alternative tryptophan degradation pathway to indole derivatives and the host aryl hydrocarbon receptor. Fungal tryptophan metabolic pathways thus cooperate with the host xenobiotic response to shape host-microbe interactions in local tissue microenvironments. • Aspergillus Idos contribute to de novo NAD+ biosynthesis and fungal growth • In conditions of tryptophan abundance, Aspergillus releases indole derivatives via Aro • Activation of lung AhR enhances harmful lung inflammation during fungal infection • Pharmacological induction of Ido in Aspergillus improves infection outcome Mammalians use the kynurenine pathway for tryptophan degradation inducing tolerogenic immune responses. Zelante et al. report that similarly, the fungus Aspergillus fumigatus uses the kynurenine pathway. Pathogenic immune response occurs when the fungus catabolizes tryptophan via the indolepyruvate pathway, which targets host AhR. Administration of Ido inducers ameliorates infection outcome. [ABSTRACT FROM AUTHOR]

New drugs and shorter regimens are needed to fight resistant forms of tuberculosis. Screening of chemical libraries for mining hit compounds is the common approach to find new antituberculars. A new medicinal chemistry and biology directed research rational has recently been successfully described by Lee and coworkers in Nature Medicine. [ABSTRACT FROM AUTHOR]

The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I 1 -type imidazoline receptors (I 1 -IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α 2 -adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α 2 -adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α 2 -adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. [ABSTRACT FROM AUTHOR]

Abstract: Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (−)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (−)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2×LD50. [Copyright &y& Elsevier]

Tuberculosis is one of the deadliest infectious diseases in the world, and the increased number of multidrug-resistant and extensively drug-resistant strains is a reason for concern. We have previously reported a series of substituted 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides with growth inhibitory activity against Mycobacterium tuberculosis strains and low propensity to be substrate of efflux pumps. Encouraged by these preliminary results, we have undertaken a medicinal chemistry campaign to determine the metabolic fate of these compounds and to delineate a reliable body of Structure–Activity Relationships. Keeping intact the (thiazol-4-yl)isoxazole-3-carboxamide core, as it is deemed to be the pharmacophore of the molecule, we have extensively explored the structural modifications able to confer good activity and avoid rapid clearance. Also, a small set of analogues based on isostere manipulation of the 2-aminothiazole were prepared and tested, with the aim to disclose novel antitubercular chemotypes. These studies, combined, were instrumental in designing improved compounds such as 42g and 42l , escaping metabolic degradation by human liver microsomes and, at the same time, maintaining good antitubercular activity against both drug-susceptible and drug-resistant strains. [Display omitted] • Structure-metabolism relationships of antitubercular 2-aminothiazoles was studied. • An extended SAR investigation of 2-aminothiazoles compounds were carried out. • Information obtained allowed the synthesis of improved analogues. • Compounds 42g and 42l coupled good activity and metabolic stability. • A novel antitubercular chemotypes is disclosed. [ABSTRACT FROM AUTHOR]