Crystal structures of non-uracil ring fragments in complex with Mycobacterium tuberculosis uracil DNA glycosylase (MtUng) as a starting point for novel inhibitor design: A case study with the barbituric acid fragment.

Uracil DNA glycosylase (UDG or Ung) is a key enzyme involved in uracil excision from the DNA as a repair mechanism. Designing Ung inhibitors is thus a promising strategy to treat different cancers and infectious diseases. The uracil ring and its derivatives have been shown to inhibit Mycobacterium tuberculosis Ung (MtUng), resulting from specific and strong binding with the uracil-binding pocket (UBP). To design novel MtUng inhibitors, we screened several non-uracil ring fragments hypothesised to occupy MtUng UBP due to their high similarity to the uracil structural motif. These efforts have resulted in the discovery of novel MtUng ring inhibitors. Here we report the co-crystallised poses of these fragments, confirming their binding within the UBP, thus providing a robust structural framework for the design of novel lead compounds. We selected the barbituric acid (BA) ring as a case study for further derivatisation and SAR analysis. The modelling studies predicted the BA ring of the designed analogues to interact with the MtUng UBP much like the uracil ring. The synthesised compounds were screened in vitro using radioactivity and a fluorescence-based assay. These studies led to a novel BA-based MtUng inhibitor 18a (IC50 = 300 µM) displaying ∼24-fold potency over the uracil ring.

Basic Nitrogen (BaN) Is a Key Property of Antimalarial Chemical Space.

Most antimalarials are based on basic N-heterocycles and possess amine functionalities. Despite this, the role of basic nitrogen (BaN) in antimalarial drug design has not been studied systematically. Our cheminformatics analysis indicates that BaN is an important feature of antimalarial space. We show that potent research antiplasmodials (RAP) and advanced-stage antimalarials (ASAMs) consistently show a higher BaN count (#BaN) compared to oral drugs. Similarly, BaN is often a vital feature of the hits obtained from phenotypic screenings despite the use of varied assay conditions. The literature review demonstrates that in several unrelated scaffolds, the addition of BaN results in enhanced antiplasmodial activity. In addition, potent antiplasmodials and HTS hits are bulky, lipophilic, and less polar and have a high aromatic ring count (#AR). This characterization of antimalarial space may be used to collate a focused compound collection to achieve higher hit rates in HTS, as shown retrospectively in this perspective.

Physicochemical Profiling and Comparison of Research Antiplasmodials and Advanced Stage Antimalarials with Oral Drugs.

To understand the property space of antimalarials, we collated a large dataset of research antiplasmodial (RAP) molecules with known in vitro potencies and advanced stage antimalarials (ASAMs) with established oral bioavailability. While RAP molecules are "non-druglike", ASAM molecules display properties closer to Lipinski's and Veber's thresholds. Comparison within the different potency groups of RAP molecules indicates that the in vitro potency is positively correlated to the molecular weight, the calculated octanol-water partition coefficient (clog P), aromatic ring counts (#Ar), and hydrogen bond acceptors. Despite both categories being bioavailable, the ASAM molecules are relatively larger and more lipophilic, have a lower polar surface area, and possess a higher count of heteroaromatic rings than oral drugs. Also, antimalarials are found to have a higher proportion of aromatic (#ArN) and basic nitrogen (#BaN) counts, features implicitly used in the design of antimalarial molecules but not well studied hitherto. We also propose using descriptors scaled by the sum of #ArN and #BaN (SBAN) to define an antimalarial property space. Together, these results may have important applications in the identification and optimization of future antimalarials.

Investigation on beneficial role of l-carnosine in neuroprotective mechanism of ischemic postconditioning in mice: possible role of histidine histamine pathway.

OBJECTIVE: The present study was undertaken to investigate the possible role of histidine-histamine pathway in the neuroprotective effects produced by L-carnosine hand in hand with ischemic postconditioning in the animal model of cerebral ischemia. METHODS: Cerebral ischemia was induced in swiss albino mice by performing BCCAO surgery. Morris water-maze test was utilized to assess the learning ability and memory of the animals. The whole brain acetylcholinesterase (AChE) activity, TBARS, GSH levels and MPO activity were evaluated as the biochemical parameters. For histopathological evaluation of the cerebral infarct size, TTC staining was employed. RESULTS: Administration of L-carnosine (500 mg/kg, i.p.) successfully attenuated the manifestations of cerebral ischemia. Higher levels of AChE, TBARS, and MPO were observed in BCCAO treated animals, which were successfully attenuated by treatment with L-carnosine and ischemic postconditioning. Whereas administration of L-carnosine and ischemic postconditioning significantly increased the level of GSH in BCCAO treated animals. Moreover, treatment with ranitidine, an H2 blocker (30 NMol, i.c.v) antagonized the neuroprotective actions of L-carnosine evidenced by decrease in MWM performance, increase in the level of AChE and oxidative stress, while decrease in GSH level in brain. The cerebral infarct size was found to be more in BCCAO inflicted animals, which was improved by the administration of L-carnosine, while the cerebral infarct size worsened by treatment with ranitidine (3 nmol, i.c.v.). CONCLUSION: It is concluded that L-carnosine exerts neuroprotective effect via involvement of histidine-histamine pathway since the beneficial effects of L-carnosine were abolished by the H2-blocker.