Novel Indane-Containing NBTIs with Potent Anti-Gram-Negative Activity and Minimal hERG Inhibition.

Novel bacterial topoisomerase inhibitors (NBTIs) make up a promising new class of antibiotics with the potential to combat the growing threat of antimicrobial resistance. Two key challenges in the development of NBTIs have been to obtain broad spectrum activity against multidrug-resistant Gram-negative bacteria and to diminish inhibition of the hERG cardiac ion channel. Here we report the optimization of a series of NBTIs bearing a novel indane DNA intercalating moiety. The addition of a basic, polar side chain connected to the indane by an ether or an N-linked secondary amide linkage together with a lipophilicity-lowering modification of the enzyme binding moiety led to compounds such as 2a and 2g which showed excellent broad spectrum potency and minimal hERG inhibition. Compound 2a demonstrated robust bactericidal in vivo activity in a mouse lung infection model with the strain P. aeruginosa ATCC 27853 which is resistant to several clinically relevant antibiotics. Rodent pharmacokinetic studies with 2a revealed an unusual profile characterized by rapid tissue distribution and a prolonged, flat terminal phase. This profile precluded further development of these compounds as potential new antibiotics.

Discovery of a Series of Indane-Containing NBTIs with Activity against Multidrug-Resistant Gram-Negative Pathogens.

The rise of multidrug-resistant (MDR) Gram-negative bacteria is a major global health problem necessitating the discovery of new classes of antibiotics. Novel bacterial topoisomerase inhibitors (NBTIs) target the clinically validated bacterial type II topoisomerases with a distinct binding site and mechanism of action to fluoroquinolone antibiotics, thus avoiding cross-resistance to this drug class. Here we report the discovery of a series of NBTIs incorporating a novel indane DNA binding moiety. X-ray cocrystal structures of compounds 2 and 17a bound to Staphylococcus aureus DNA gyrase-DNA were determined, revealing specific interactions with the enzyme binding pocket at the GyrA dimer interface and a long-range electrostatic interaction between the basic amine in the linker and the carboxylate of Asp83. Exploration of the structure-activity relationship within the series led to the identification of lead compound 18c, which showed potent broad-spectrum activity against a panel of MDR Gram-negative bacteria.

Migraine aura-like symptoms at onset of stroke and stroke-like symptoms in migraine with aura.

Background and objectives: In general, suddenly occurring neurological deficits, i.e., negative neurological symptoms, are considered symptoms of focal cerebral ischemia, while positive irritative symptoms with gradual onset are viewed as the characteristics of migraine aura. Nevertheless, cortical spreading depolarization, the pathophysiological basis of migraine aura, has also been observed in acute ischemic stroke. The aim of our study was to determine the frequency of migraine aura-like symptoms at ischemic stroke onset and stroke-like symptoms in migraine with aura. Methods: We interviewed 350 consecutive patients with ischemic stroke and 343 with migraine with aura using a structured questionnaire. Stroke diagnosis was confirmed by imaging, and migraine with aura was diagnosed according to the current criteria of the International Headache Society. Patients with wake-up strokes or severe cognitive deficits that precluded a useful interview were excluded from the study. Results: Seventy-eight patients with stroke (22.3%) reported visual symptoms, 145 (41.4%) sensory symptoms, 197 (56.3%) a paresis, and 201 patients (57.4%) more than one symptom, compared to 326 migraine patients with aura (95%) with visual symptoms (P < 0.001), 175 (51%) with sensory symptoms (p = 0.011), 50 (14.6%) with paresis (P < 0.001), and 211 (61.5%) with more than one symptom (p = 0.27). Among patients with stroke, migraine-like symptoms were frequent: 36 patients (46.2%) with visual disturbance and 78 (53.8%) with sensory symptoms experienced irritative sensations. Paresis-onset in stroke lasted longer than 5 min in 43 patients (21.8%). Spreading of sensory and motor symptoms occurred in 37 (25.5%) and 37 (18.8%) patients, respectively. Stroke-like negative symptoms in migraine with aura occurred in 39 patients (12%) with visual symptoms, in 55 (31.4%) with sensory symptoms, and paresis appeared suddenly in 14 patients (28%). More than one symptom in succession occurred in 117 patients with stroke (58.2%) and in 201 migraine with aura patients (95.3%; P < 0.001). Conclusion: Many patients with stroke experience migraine-like symptoms at stroke onset, and many migraine with aura patients have stroke-like symptoms. Though overall the symptom frequencies of the two groups are significantly different, clarifying the differential diagnosis in an individual patient requires additional history elements, physical findings, or results of ancillary investigations.

Symptoms and patterns of symptom propagation in incipient ischemic stroke and migraine aura.

Background and objectives: Taking a detailed history of symptoms is important for differentiating incipient ischemic stroke and migraine aura. The aim of our study is to describe in detail symptom type and temporal pattern of symptom evolution (i.e., symptom succession and the time lapse between symptoms) and to identify differentiating clinical features in patients with ischemic stroke and migraine with aura. Methods: Consecutive patients with ischemic stroke and migraine with aura were interviewed using a structured questionnaire. Stroke diagnosis was confirmed by imaging and migraine with aura was diagnosed according to the current criteria of the International Headache Society. Wake-up strokes and patients with severe cognitive deficits were excluded. Results: In stroke patients and migraine patients, respectively, 50/78 (64%) vs. 123/326 (37%) had one, 18 (23%) vs. 127 (38%) had two, 5 (6%) vs. 69 (21%) had three, 2 (2%) vs. 4 (1%) had four, and 3 (3%) vs. 3 (1%) had five visual symptoms. In respect of sensory symptoms, 76/145 (52.4%) vs. 116/175 (66%) reported paresthesia and 92/145 (63.4%) vs. 132 (75%) numbness. Looking at the beginning, visual symptoms were the first symptom more often in migraine aura than in ischemic stroke (72.1 vs 18.8%, P < 0.001; PPV 86.8%). Sensory (29 vs 13.9%, P = 0.001; PPV 54.8%) and motor symptoms (20.5 vs 1.4%, P < 0.001; PPV 88.9%) were the first symptom more frequently in ischemic stroke. Of patients with consecutive symptoms, 39 of 201 (19%) compared to 34 of 117 (29%) (P = 0.02; PPV 46.6%) reported at least two simultaneous symptoms. A time lapse between symptoms of < 1 min (18.6 vs 6.3%, P < 0.001; PPV 57.1%) and > 360 min (15.8 vs 0%, χ2 = 39.61, P < 0.001; PPV 100%) was more frequent in stroke whereas a time lapse between 5 and 60 min was more frequent in migraine aura (41.1 vs 68.7%, χ2 = 23.52, P < 0.001; PPV 78.7%). Conclusion: There is a significant overlap in the clinical presentation of stroke and migraine aura. In particular, a substantial proportion of patients in one group had symptoms that are traditionally attributed to the other group. This study highlights the similarities and differences between symptoms of ischemic stroke and migraine aura and challenges our reasoning in daily clinical practice.

A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus Activity In Vitro.

Antiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A viruses (seasonal and 2009 pandemic H1N1 and seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in Madin-Darby canine kidney (MDCK) cells with nanomolar to submicromolar 50% effective concentrations (EC50s), low toxicity, and favorable selective indices. RO-7 also inhibited influenza virus replication in primary normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B viruses in multiple in vitro assays, supporting its further characterization and development as a potential antiviral agent for treating influenza.

Photocatalytic synthesis of allylic trifluoromethyl substituted styrene derivatives in batch and flow.

A cobalt-catalyzed photochemical synthesis of allylic trifluoromethanes from styrene derivatives using 2,2,2-trifluoroethyl iodide is described. The method complements existing approaches, providing an alternative bond construction strategy to access these compounds. The process may be conducted in continuous mode in a novel photochemical flow reactor, resulting in a notable productivity increase.

Total synthesis of (-)-dendrobine.

Cascading to alkaloids: an 18-step total synthesis of (-)-dendrobine is based on a reaction cascade with a key amine group. The amine is the initiator of the cascade and provides an efficient method for installing the stereocenters at C11 and C3. The overall transformation occurs stereoselectively only when the conversion is carried out without the isolation of intermediates.