Susanta Adhikari

Abstract: A series of 2‘ ‘-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit μM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.

Abstract: Strategically modified4-(diethylamino)-2-(pyridin-2-ylmethoxy)benzaldehyde appended BODIPY-based probe N,N-SP-BPY detects aspartic acid (Asp) and glutamic acid (Glu) by inhibition of Photoinduced electron transfer (PET) process in water. The probe shows considerable and rapid fluorescence enhancement upon addition of Asp and Glu. Additionally, a distinct colorimetric change from pink to a colorless solution can be observed to recognize traces of Asp and Glu. The probe detects Asp and Glu as low as 1 μM and 5 μM respectively. Furthermore, the probe can efficiently detect intracellular Asp and Glu in live HeLa, A549, MDA-MB-468 and HEK-293T cells under fluorescence microscope without showing any cytotoxic effect. Two model BODIPY derivatives are also synthesized to establish strategic modification. 1H NMR titration and theoretical calculations strongly supports experimental findings.

Abstract: A 2-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)acetaldehydeanchored rhodamine B based probe, RDNAP detects Cr3+ ion by fluorescence resonance energy transfer (FRET) process in aqueous buffered acetonitrile media (7:3, v/v). Conversely, conjugation of 2-(1,3-dioxo-6-(piperidin-1-yl)-1H-benzo[de]isoquinolin-2(3H)-yl)acetaldehyde with rhodamine B provides another probe, RDNAP-PY that undergoes Cr3+assisted ratiometric fluorescence and colorimetric change in the same media. RDNAP-PY provides higher FRET efficiency and detects as low as 1.81×10−6 M Cr3+with an association constant, 15.9 × 104 M−1. Other common ions do not interfere. RDNAP-PY efficiently images intracellular Cr3+ in live Hep3B, MCF-7, HeLa, SiHa and HEK 293T cells under fluorescence microscope in a ratiometric and time dependent manner. 1H NMR titration and DFT studies strongly support experimental findings.

Abstract: The devastating appearance of numerous drug-unresponsive strains of Leishmania donovani and severe toxic side effects of conventional antileishmanial therapy necessitates the search for novel leads, to treat visceral leishmaniasis efficiently. The current study deals with the synthesis and biological evaluation of a unique C-5 functionalized oxindole based polyphenol to ascertain its activities against L. donovani infection, in vitro. The polyhydroxylated oxindole derivative (1) was generated by coupling styrene derivatives with 5-bromo bis-arylidene oxindole using Heck coupling reaction. The synthesized molecule 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Molecule 1 showed promising anti-promastigote and anti-amastigote activities with IC50 values 15 µM and 1 µM, respectively, with no cytotoxicity towards host splenocytes. The results revealed that this compound induced parasite death by promoting oxidative stress, thereby triggering apoptosis.

Abstract: The recognition of a specific protein in blood serum amidst similar proteins is a challenging and vital endeavor in clinical diagnostics. Herein, we have described a small-molecule probe (DFPAC-OH)...

Abstract: Although aminoglycosides have been used as antibacterials for decades, their use has been hindered by their inherent toxicity and the resistance that has emerged to these compounds. It seems that such issues have relegated a formerly front-line class of antimicrobials to the proverbial back shelf. However, recent advances have demonstrated that novel aminoglycosides have a potential to overcome resistance as well as to be used to treat HIV-1 and even human genetic disorders, with abrogated toxicity. It is not the end for aminoglycosides, but rather, the challenges faced by researchers have led to ingenuity and a change in how we view this class of compounds, a renaissance.

Abstract: Aminoglycosides are highly potent, broad-spectrum antibiotics that exert their bactericidal therapeutic effect by selectively binding to the decoding aminoacyl site (A-site) of the bacterial 16 S rRNA, thereby interfering with translational fidelity during protein synthesis. The appearance of bacterial strains resistant to these drugs, as well as their relative toxicity, have inspired extensive searches towards the goal of obtaining novel molecular designs with improved antibacterial activity and reduced toxicity. In the last few years, a new, aminoglycoside dependent therapeutic approach for the treatment of certain human genetic diseases has been identified. These treatments rely on the ability of certain aminoglycosides to induce mammalian ribosomes to readthrough premature stop codon mutations. This new and challenging task has introduced fresh research avenues in the field of aminoglycoside research. Recent observations and current challenges in the design of aminoglycosides with improved antibacterial activity and the treatment of human genetic diseases are discussed.

Abstract: Hereunder, we highlight bacterial membrane anionic lipids as attractive targets in the design of antibacterial drugs which can be effective against both Gram-positive and Gram-negative resistant bacteria. In this approach, first, molecular foundations and structure–activity relationships are laid out for membrane-targeting drugs and drug candidates from the structure and physicochemical properties of the main membrane targets, describing, as well, the corresponding identified resistances. Second, this approach is illustrated by the history of the emergence of antibacterial and antifungal amphiphilic aminoglycosides (AAGs) which are active against Gram-positive and Gram-negative resistant bacteria. AAGs have resulted from intensive medicinal chemistry development of a group of old antibiotic drugs known as aminoglycosides (AGs), which target ribosomal RNA. The aforementioned AAG's are being used towards discovering new antibiotics which are less toxic and less susceptible to resistance. The recent results in the field of AAGs are described and discussed in terms of structure–activity relationships and mechanism of action.

Abstract: Shortly after the discovery of the first antibiotics, bacterial resistance began to emerge. Many mechanisms give rise to resistance; the most prevalent mechanism of resistance to the aminoglycoside (AG) family of antibiotics is the action of aminoglycoside-modifying enzymes (AMEs). Since the identification of these modifying enzymes, many efforts have been put forth to prevent their damaging alterations of AGs. These diverse strategies are discussed within this review, including: creating new AGs that are unaffected by AMEs; developing inhibitors of AMEs to be co-delivered with AGs; or regulating AME expression. Modern high-throughput methods as well as drug combinations and repurposing are highlighted as recent drug-discovery efforts towards fighting the increasing antibiotic resistance crisis.

Abstract: The lack of absolute prokaryotic selectivity of natural antibiotics is widespread and is a significant clinical problem. The use of this disadvantage of aminoglycoside antibiotics for the possible treatment of human genetic diseases is extremely challenging. Here, we have used a combination of biochemical and structural analysis to compare and contrast the molecular mechanisms of action and the structure-activity relationships of a new synthetic aminoglycoside, NB33, and a structurally similar natural aminoglycoside apramycin. The data presented herein demonstrate the general molecular principles that determine the decreased selectivity of apramycin for the prokaryotic decoding site, and the increased selectivity of NB33 for the eukaryotic decoding site. These results are therefore extremely beneficial for further research on both the design of new aminoglycoside-based antibiotics with diminished deleterious effects on humans, as well as the design of new aminoglycoside-based structures that selectively target the eukaryotic ribosome.