We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

Bacterial resistance is a growing problem worldwide and is estimated that deaths by infectious diseases associated with resistant pathogens will generate 10 million deaths per year in 2050. This problem becomes more serious due to the low level of research and development of new drugs, which has fallen drastically in the last 40 years. For example, in the last decade of a total of 293 new drugs approved by the FDA, only 9 corresponded to antimicrobial drugs and none constituted a new structural class. The majority of the molecules in the clinical phase II or III, coming from modifications of drugs in clinical use, this strategy makes easier the bacterial susceptibility to generate resistance through the mechanisms expressed for their drug predecessors. Under this scenario, it is urgent to generate the most novel strategies for the development of antibacterial compounds with new targets or mechanism of action, without a structural relationship with the antibiotic drugs predecessors. Under this look, the present review addresses the development of the latest antibacterial drugs in clinical phases II and III, analyzing the design strategies by which these new molecules were obtained and the structure-activity relationship of these new families of antibiotics, in order to define the state of the vanguard antibacterial drugs in the post-antibiotic era.

Since the Hedgehog signaling pathway has been associated with cancer, it has emerged as a therapeutic target for cancer therapy. The main target among the key Hedgehog proteins is the GPCR-like Smo receptor. Therefore, some Smo antagonists that have entered clinical trials, including the US FDA-approved drugs vismodegib and sonidegib, to treat basal cell carcinoma and medulloblastoma. However, early resistance of these drugs has spawned the need to understand the molecular bases of this phenomena. We therefore reviewed details about Smo receptor structures and the best Smo antagonist chemical structures. In addition, we discussed strategies that should be considered to develop new, safer generations of Smo antagonists that avoid current clinical limitations.