In This Issue Cite This: ACS Med. Chem. Lett. 2017, 8, 1128-1128
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HIV-1 ENTRY INHIBITORS: ALOPERINE DERIVATIVES Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS) and related opportunistic infections, a serious health problem that affects more than 30 million people worldwide. Current combination antiretroviral therapies (cART) combine drugs targeting different steps of the HIV life cycle. These treatments successfully delay the progression of HIV infection, in particular, in early stages of the disease. However, drug resistance, cross resistance, adverse effects, and toxicity problems emerge during cART regimens and prompt the search for new anti-HIV drugs. Chen and co-workers (DOI: 10.1021/acsmedchemlett.7b00376) report herein their optimization efforts of aloperine derivatives as HIV-1 entry inhibitors. The authors previously identified aloperine derivatives that inhibited HIV-1 entry at low micromolar concentrations. The present study focused on improving antiviral potency through structural optimizations of aloperine and its derivatives. The most potent compound of this series demonstrated a 15-fold increase in potency and displayed a good selectivity index. A mechanism of action study demonstrated that inhibition of HIV-1 entry occurs at a step after CD4 binding but before membrane fusion. These results highlight the potential of aloperine derivatives as a new class of HIV-1 entry inhibitors.
thiosemicarbazones were in accordance with their in vivo data, which revealed a significant reduction in hemorrhage induced by B. pauloensis venom. NMR spectra showed that an interaction occurs between the enzyme’s Zn(II) and the ligand’s thiosemicarbazone group. These findings pave the way for the use of these types of compounds in combination with serum therapy.
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ANTIMYCOBACTERICIDAL AGENTS: INDOLYLALKYLTRIPHENYLPHOSPHONIUM AGENTS Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), an infectious disease that is among the ten leading causes of death worldwide. The success of TB treatment depends on the location of the infection, MDR drug resistance, and overall health and age of the patient. A major drawback is the standard length of time for a course of TB treatment of about 6 months. Go and co-workers (DOI: 10.1021/acsmedchemlett.7b00287) report herein the synthesis of mycobactericidal indole derivatives bearing a triphenylphosphonium (TPP) tail. This design was based on the membrane-targeting ability of the TPP cation. The two most active indolylalkyl TPP compounds caused a loss in the membrane potential of treated mycobacteria in vitro. The authors propose that these compounds elicit their bactericidal effects by impairing electron transport and slowing down production of energy in the mycobacterial cell in addition to affecting cell division. The findings by Go’s group show the potential of indolylalkyl TPPs as antimycobacterial drugs that exert their effects through depolarization of the Mycobacterium membrane.
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HEMORRHAGE TREATMENT IN SNAKEBITES: THIOSEMICARBAZONE METALLOPROTEINASE INHIBITORS Snake venom contains various toxins, such as snake venom metalloproteinases (SVMPs), which are zinc-dependent proteolytic enzymes that cause hemorrhage and subsequent tissue damage in snake bite victims. Current treatment options for snake bites involve the use of antivenoms; however, their effectiveness is limited, and they can elicit undesired side effects. Thus, inhibitors to specific toxins within snake venoms would provide a better alternative to current antivenom treatments. In this issue, Sant’Anna and co-workers (DOI: 10.1021/ acsmedchemlett.7b00186) report the design and synthesis of inhibitors of snake venom metalloproteinases (SVMPs) bearing a thiosemicarbazone moiety. Homology 3D modeling used the SVMP sequence isolated from Bothrops pauloensis venom. This led to the design, synthesis, and in vitro evaluation of thiosemicarbazones with inhibitory activity against the SVMP of B. pauleonsis. The in vitro results of the two most active © 2017 American Chemical Society
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Published: November 9, 2017 1128
DOI: 10.1021/acsmedchemlett.7b00441 ACS Med. Chem. Lett. 2017, 8, 1128−1128
