Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are “capsid binders” that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo–electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens.

A series of (2E)-1-(5-bromothiophen-2-yl)-3-(para-substituted phenyl)prop-2-en-1-ones (TB1-TB11) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO-B except (2E)-1-(5-bromothiophen-2-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TB7) and (2E)-1-(5-bromothiophen-2-yl)-3-(4-chlorophenyl)prop-2-en-1-one (TB8), which were selective inhibitors of hMAO-A. The most potent compound, (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1-one (TB5), showed the best inhibitory activity and higher selectivity toward hMAO-B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood-brain barrier. Moreover, the most potent MAO-B inhibitor, TB5, was found to be nontoxic at 5 and 25 μm, with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.

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A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4-13, were synthesized and tested for their human MAO inhibitory activity. All the compounds were found to be selective and reversible toward hMAO-A except 4, a selective inhibitor of hMAO-B and 12, a nonselective inhibitor. Compound 7 was found to be a potent inhibitor of hMAO-A with Ki = 0.06 ± 0.003 μM and was having selectivity index of (SI = 1.02 × 10(-5)). It was found to be better than standard drug, Moclobemide (hMAO-A with Ki = 0.11 ± 0.01 μM) with selectivity index of SI = 0.049. Molecular docking simulation was carried out to understand the crucial interactions responsible for selectivity and potency.

Drugs inhibiting the iron scarcity-induced, siderophore-mediated iron scavenging systems of Mycobacterium tuberculosis (Mtb) and Yersinia pestis (Yp) may provide new therapeutic lines of defense. Compounds with structural similarities to siderophores were synthesized and evaluated as antimicrobials against Yp and Mtb under iron limiting conditions, which mimic the iron scarcity these pathogens encounter and must adapt to in the host, and under standard iron rich conditions for comparison. New antimicrobials were identified, some of which warrant exploration as initial leads against potentially novel targets and small-molecule tools to assist in the elucidation of targets specific to iron-scarcity adapted Yp and Mtb. KeywordsSiderophore; Antimicrobial; drug target; Mycobacterium tuberculosis; Yersinia pestis; arylcarbothioamide-pyrazolines Mtb, the etiologic agent of tuberculosis, and Yp, the causative agent of plague and a potential agent of biowarfare and bioterrorism, are pathogens with serious impacts on global public health. MDR tuberculosis is an emerging pandemic and the surfacing of extensive drugresistant (XDR) tuberculosis poses a new global threat. 1,2 Plague is a re-emerging disease and the occurrence of MDR Yp strains and self-transferable Yp plasmids conferring antibiotic resistance raises concerns about future plague control. 3,4 These scenarios underscore the need for expanding the anti-tuberculosis and anti-plague drug repertoires. Anti-infective drugs against in vivo conditionally essential targets may offer novel therapeutic possibilities, help the fight against MDR/XDR strains and the prevention of their selection and dissemination, and increase biodefense preparedness. 5 *Corresponding authors: LENQ: Tel.: +1 212 746 4497, e-mail: leq2001@med.cornell.edu; JV: Tel.: +91-651-2275843, e-mail: venkatesanj@bitmesra.ac.in. † These authors contributed equally Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access, their production is induced under iron scarcity, and they are believed to be required for scavenging iron inside the host, where free iron is scarce (10 −25 -10 −15 M) and pathogens experience iron-limiting conditions. 6,7 The Mtb siderophore-deficient mutant is impaired for growth in macrophages and iron-limiting culture medium. 8 The Mtb mutant lacking the IrtAB ferri-siderophore uptake system is impaired for multiplication in macrophages, mouse lung, and iron-limiting medium. 9 Siderophore system-deficient Yp strains are avirulent in mice infected subcutaneously (a route imitating the fleabite transmission of Yp) and unable t...

The alarming rise in drug-resistant clinical cases of tuberculosis (TB) has necessitated the rapid development of newer chemotherapeutic agents with novel mechanisms of action. The mycobactin biosynthesis pathway, conserved only among the mycolata family of actinobacteria, a group of intracellularly surviving bacterial pathogens that includes Mycobacterium tuberculosis, generates a salicyl-capped peptide mycobactin under ironstress conditions in host macrophages to support the iron demands of the pathogen. This in vivo essentiality makes this less explored mycobactin biosynthesis pathway a promising endogenous target for novel lead-compounds discovery. In this Perspective, we have provided an up-to-date account of drug discovery efforts targeting selected enzymes (MbtI, MbtA, MbtM, and PPTase) from the mbt gene cluster (mbtA-mbtN). Furthermore, a succinct discussion on non-specific mycobactin biosynthesis inhibitors and the Trojan horse approach adopted to impair iron metabolism in mycobacteria has also been included in this Perspective.