Microbiome and host crosstalk: A new paradigm to cancer therapy.

The commensal microbiome of humans has co-evolved for thousands of years. The microbiome regulates human health and is also linked to several diseases, including cancer. The advances in next-generation sequencing have significantly contributed to our understanding of the microbiome and its association with cancer and cancer therapy. Recent studies have highlighted a close relationship of the microbiome to the pharmacological effect of chemotherapy and immunotherapy. The chemo-drugs usually interfere with the host immune system and reduces the microbiome diversity inside the body, which in turn leads to decreased efficacy of these drugs. The human microbiome, specifically the gut microbiome, increases the potency of chemo-drugs through metabolism, enzymatic degradation, ecological differences, and immunomodulation. Recent research exploits the involvement of microbiome to shape the efficacy and decrease the toxicity of these chemo-drugs. In this review, we have highlighted the recent development in understanding the relationship of the human microbiome with cancer and also emphasize on various roles of the microbiome in the modulation of cancer therapy. Additionally, we also summarize the ongoing research focussed on the improved efficacy of chemotherapy and immunotherapy using the host microbiome.

Natural Bioactive Thiazole-Based Peptides from Marine Resources: Structural and Pharmacological Aspects.

Peptides are distinctive biomacromolecules that demonstrate potential cytotoxicity and diversified bioactivities against a variety of microorganisms including bacteria, mycobacteria, and fungi via their unique mechanisms of action. Among broad-ranging pharmacologically active peptides, natural marine-originated thiazole-based oligopeptides possess peculiar structural features along with a wide spectrum of exceptional and potent bioproperties. Because of their complex nature and size divergence, thiazole-based peptides (TBPs) bestow a pivotal chemical platform in drug discovery processes to generate competent scaffolds for regulating allosteric binding sites and peptide-peptide interactions. The present study dissertates on the natural reservoirs and exclusive structural components of marine-originated TBPs, with a special focus on their most pertinent pharmacological profiles, which may impart vital resources for the development of novel peptide-based therapeutic agents.

Insight into the interaction of benzothiazole tethered triazole analogues with human serum albumin: Spectroscopy and molecular docking approaches.

The interaction of four benzothiazole tethered triazole analogues (MS43, MS70, MS71, and MS78) with human serum albumin (HSA) was investigated using various spectroscopic techniques (ultraviolet-visible (UV-vis) light absorption, fluorescence, circular dichroism (CD), molecular docking and density functional theory (DFT) studies). Fluorescence quenching constants (~1012 ) revealed a static mode of quenching and binding constants (Kb ~104 ) indicating the strong affinity of these analogues for HSA. Further alteration in the secondary structure of HSA in the presence of these analogues was also confirmed by far UV-CD spectroscopy. The intensity loss in CD studied at 222 nm indicated an increase in random coil/ß-sheet conformations in the protein. Binding energy values (MS71 (-9.3 kcal mol-1 ), MS78 (-8.02 kcal mol-1 ), MS70 (-7.16 kcal mol-1 ) and MS43 (-6.81 kcal mol-1 )) obtained from molecular docking revealed binding of these analogues with HSA. Molecular docking and DFT studies validated the experimental results, as these four analogues bind with HSA at site II through hydrogen bonding and hydrophobic interactions.

An expedient approach to 1,2-dihydroisoquinoline derivatives via cobalt catalysed 6-endo dig cyclization followed by Mannich condensation of o-alkynylarylaldimines.

A highly effective 6-endo dig cyclisation of o-alkynylaldimines to 1,2-dihydroisoquinolines has been described via direct and nitro Mannich condensation using inexpensive and readily available cobalt chloride as catalyst. This strategy provides an effective procedure for the synthesis of substituted 1,2-dihydroisoquinolines derivatives in moderate to high yields. An addition of pronucleophiles, such as nitromethane, acetone and α-hydroxyacetone, to o-alkynylarylaldimines has been achieved via isoquinolinium intermediate.

Synthesis of ciprofloxacin-linked 1,2,3-triazole conjugates as potent antibacterial agents using click chemistry: exploring their function as DNA gyrase inhibitors via in silico- and in vitro-based studies.

The antibacterial efficacy of some newly developed C-3 carboxylic group-containing ciprofloxacin-linked 1,2,3-triazole conjugates was studied. Twenty-one compounds from three different series of triazoles were synthesized using click chemistry and evaluated for their antibacterial activity against nine different pathogenic strains, including three Gram-positive strains, i.e. Enterococcus faecalis (ATCC29212), Staphylococcus aureus (ATCC25923), Staphylococcus epidermidis (clinical isolate), and six Gram-negative bacterial strains, i.e. Escherichia coli (ATCC25922), Pseudomonas aeruginosa (ATCC27853), Salmonella typhi (clinical isolate), Proteus mirabilis (clinical isolate), Acinetobacter baumannii (clinical isolate) and Klebsiella pneumonia (clinical isolate). Among the compounds, 10, 10a, 10b, 10c, 10d, 11a, 11f, 12c, 12e and 12f showed excellent activity with MIC values upto 12.5 µg mL-1, whereas the control ciprofloxacin showed MIC values of 0.781-25 µg mL-1 towards various strains. In addition, the low toxicity profile of the synthesized molecules revealed that they are potent antibiotics. Molecular docking and MD analysis were performed using the protein structure of E. coli DNA gyrase B, which was further corroborated with an in vitro assay to evaluate the inhibition of DNA gyrase. The analysis revealed that compound 10b was the most potent inhibitor of DNA gyrase compared to ciprofloxacin, which was employed as the positive control. Furthermore, the structure of two title compounds (11a and 12d) was characterized using single-crystal analysis.

Is structural hybridization invoking new dimensions for antimalarial drug discovery research?

Despite effective prevention methods, malaria is a devastating, persistent infection caused by protozoal parasites that result in nearly half a million fatalities annually. Any progress made thus far in the eradication of the disease is jeopardized by the expansion of malaria parasites that have evolved to become resistant to a wide range of drugs, including first-line therapy. To surmount this significant obstacle, it is necessary to develop newly synthesized drugs with multiple modes of action that may have a novel target in various stages of Plasmodium parasite development and this is made possible by the hybridization concept. Hybridization is the combination of at least two diverse pharmacophore units with some linkers bringing about a single molecule with a diverse mode of action. It intensifies a drug's physiological and chemical characteristics, such as absorption, cellular target contact, metabolism, excretion, distribution, and toxicity. This review article outlines the currently published most potent hybrid drugs against the Plasmodium species.

Ciprofloxacin-Tethered 1,2,3-Triazole Conjugates: New Quinolone Family Compounds to Upgrade Our Antiquated Approach against Bacterial Infections.

A newer ciprofloxacin series containing 1,2,3-triazole conjugates of ciprofloxacin was designed, synthesized, and well characterized using modern analytical techniques by reacting diversified anilines with ciprofloxacin obtained from ciprofloxacin hydrochloride. The newer conjugates were evaluated for their antimicrobial activity against various strains, viz. Staphylococcus aureus (ATCC25923), Enterococcus faecalis (clinical isolate), Staphylococcus epidermidis (ATCC3594), Escherichia coli (ATCC25922), Pseudomonas aeruginosa (ATCC27853), Salmonella typhi (clinical isolate), Salmonella typhimurium (clinical isolate), Acinetobacter baumannii (ATCC19606), Aeromonas hydrophila (ATCC7966), Plesiomonas shigelloides (ATCC14029), and Sphingo biumpaucimobilis (MTCC6362) in vitro. Interestingly, some of the conjugates showed superior antimicrobial activity as compared to the control drug ciprofloxacin. The three compounds 4i, 4j, and 4n showed strong activity with minimum inhibitory concentration (MIC) 0.78 µM, while the compound 4g showed MIC 1.56 µM against S. typhi (clinical). The compound 4a showed good efficacy against S. aureus (ATCC25923) and S. typhi (clinical) with MIC 3.12 µM, while the compound 4b exhibited efficacy with MIC 3.12 µM against S. aureus (ATCC25923) and the control drug ciprofloxacin showed MIC 6.25 µM. Among all of the synthesized compounds, 4e, 4f, 4g, 4h, 4p, 4q, 4t, and 4u displayed less than 20% hemolysis, while the rest of the compounds showed hemolysis in the range of 21-48%. Moreover, the structure of compound 4b was also established by single-crystal X-ray diffraction studies.

Challenges and Recent Advances of Novel Chemical Inhibitors in Medulloblastoma Therapy.

Medulloblastoma is a common term used for the juvenile malignant brain tumor, and its treatment is exciting due to different genetic origins, improper transportation of drug across the blood-brain barrier, and chemo-resistance with various side effects. Currently, medulloblastoma divided into four significant subsections (Wnt, Shh, Group 3, and Group 4) is based on their hereditary modulation and histopathological advancement. In this chapter, we tried to combine several novel chemical therapeutic agents active toward medulloblastoma therapy. All these compounds have potent activity to inhibit the medulloblastoma.

Neurocysticercosis and its impact on crude prevalence rate of epilepsy in an Indian community.

BACKGROUND: Community-based studies of epilepsy in India have reported variable prevalence rates, 5-10/1000 population. Reasons for this wide variation in the prevalence rates are uncertain. Most of the earlier studies had not done appropriate investigations to establish the possible etiology. AIM: To study the prevalence and etiological profile of active epilepsy in the rural population of Uttarakhand. MATERIAL AND METHODS: In this rural community-based study in the state of Uttarakhand, a door-to-door survey was conducted using validated questionnaire. All the suspected cases of epilepsy were examined by a neurologist to confirm the diagnosis of epilepsy and all the confirmed cases underwent contrast computed tomography (CT) scan and electroencephalography (EEG). Epilepsy and epilepsy syndromes were classified using the classifications proposed by the International League Against Epilepsy. RESULTS: Of the 14,086 population studied, 141 cases of active epilepsy were detected giving a crude prevalence rate of 1%. After clinical evaluation and scanning, 35 (24.8%) were found to have seizure disorder active neurocysticercosis (NCC) and 14 (9.9%) had remote symptomatic seizures related to calcified granuloma. After excluding acute and remote symptomatic cases related to NCC, prevalence rate of epilepsy was 6.5/1000. CONCLUSION: The study suggests that the region-specific prevalence rates of epilepsy in India are partly dependent on the prevalence of NCC in the given community. To some extent, this may be responsible for variable rates of epilepsy prevalence reported from different regions of the country.

Benzyl N-(3-chloro-4-fluoro-phen-yl)carbamate.

The title compound, C(14)H(11)ClFNO(2), the phenyl ring (A), the chloro-fluoro-phenyl ring (B) and the central ketone O/C/O group (C) are not coplanar, with dihedral angles B/C = 31.6 (2), A/B = 21.3 (2) and A/C = 50.1 (2)°. The crystal packing is stabilized by N-H⋯O and C-H⋯O inter-actions.

1-Prop-2-ynyl-1H-benzimidazol-2-amine.

In the title compound, C(10)H(9)N(3), the benzimidazol-2-amine and CH(2)-C CH units are not coplanar, with a dihedral angle of 60.36° between their mean planes. The crystal structure is stabilized by inter-molecular N-H⋯N hydrogen bonding and π-π inter-actions [centroid-centroid distances 3.677 (1) and 3.580 (1) Å], assembling the mol-ecules into a supra-molecular structure with a three-dimensional network.

tert-Butyl N-{2-[bis-(prop-2-yn-1-yl)amino]-phen-yl}carbamate.

In the crystal of the title compound, C(17)H(20)N(2)O(2), the molecules are linked by C-H⋯O interactions. Intra-molecular C-H⋯O and N-H⋯N hydrogen bonds also occur.

2-(4-Chloro-phen-yl)chromen-4-one.

The title compound, C(15)H(9)ClO(2), is a synthetic flavonoid obtained by the cyclization of 3-(4-chloro-phen-yl)-1-(2-hy-droxy-phen-yl)prop-2-en-1-one. The 4-chloro-phenyl ring is twisted at an angle of 11.54° with respect to the chromen-4-one skeleton. In the crystal, pairs of mol-ecules are inter-connected by weak Cl⋯Cl inter-actions [3.3089 (10) Å] forming dimmers which are further peripherally connected through inter-molecular C-H⋯O hydrogen bonds.

(2E)-1-(4-Amino-phen-yl)-3-(2,4-dichloro-phen-yl)prop-2-en-1-one.

The title compound, C(15)H(11)Cl(2)NO, is approximately planar (r.m.s. deviation = 0.062 Å) and contains a single C=C double bond in a trans (E) configuration. The crystal packing is stabilized by intermolecular N-H⋯N and N-H⋯O inter-molecular hydrogen bonding.

N-(Prop-2-yn-1-yl)-1,3-benzothia-zol-2-amine.

In the title compound, C(10)H(8)N(2)S, the 2-amino-benzothia-zole and propyne groups are not coplanar [dihedral angle = 71.51 (1)°]. The crystal structure is stabilized by strong inter-molecular N-H⋯N hydrogen bonds and C-H⋯C, C-H⋯π and F-type aromatic-aromatic [centroid-centroid distance = 3.7826 (12) Å] inter-actions are also observed.

Natural Thiazoline-Based Cyclodepsipeptides from Marine Cyanobacteria: Chemistry, Bioefficiency and Clinical Aspects.

BACKGROUND: Peptides and peptide-based therapeutics are biomolecules that demarcate a significant chemical space to bridge small molecules with biological therapeutics, such as antibodies, recombinant proteins, and protein domains. INTRODUCTION: Cyclooligopeptides and depsipeptides, particularly cyanobacteria-derived thiazoline-based polypeptides (CTBCs), exhibit a wide array of pharmacological activities due to their unique structural features and interesting bioactions, which furnish them as promising leads for drug discovery. METHODS: In the present study, we comprehensively review the natural sources, distinguishing chemistries, and pertinent bioprofiles of CTBCs. We analyze their structural peculiarities counting the mode of actions for biological portrayals which render CTBCs as indispensable sources for emergence of prospective peptide-based therapeutics. In this milieu, metal organic frameworks and their biomedical applications are also briefly discussed. To boot, the challenges, approaches, and clinical status of peptide-based therapeutics are conferred. RESULTS: Based on these analyses, CTBCs can be appraised as ideal drug targets that have always remained a challenge for traditional small molecules, like those involved in protein- protein interactions or to be developed as potential cancer-targeting nanomaterials. Cyclization-induced reduced conformational freedom of these cyclooligopeptides contribute to improved metabolic stability and binding affinity to their molecular targets. Clinical success of several cyclic peptides provokes the large library-screening and synthesis of natural product-like cyclic peptides to address the unmet medical needs. CONCLUSION: CTBCs can be considered as the most promising lead compounds for drug discovery. Adopting the amalgamation of advanced biological and biopharmaceutical strategies might endure these cyclopeptides to be prospective biomolecules for futuristic therapeutic applications in the coming times.

Efficient N-formylation of primary aromatic amines using novel solid acid magnetic nanocatalyst.

Sulfonic acid functionalized over biguanidine fabricated silica-coated heterogeneous magnetic nanoparticles (NP@SO3H) have been synthesized, well characterized and explored for the first time, as an efficient and recyclable catalyst for N-formylation of primary amines under mild reaction conditions. Exploiting the magnetic nature of Fe3O4, the prepared catalyst was readily recovered from the reaction mixture via an external magnet. The catalyst can be reused for up to six cycles without any substantial loss of catalytic activity. The cost effectiveness, simple methodology, wide substrate tolerance, excellent yield and easy work-up are the additional advantages of present catalytic system.

Insights into the interaction of potent antimicrobial chalcone triazole analogs with human serum albumin: spectroscopy and molecular docking approaches.

Mechanistic insights into the interaction of five previously chemically synthesized triazole-linked chalcone analogs (CTs) with human serum albumin (HSA) were sought using various spectroscopic techniques (UV-visible absorption, fluorescence, and circular dichroism) and molecular docking. The fluorescence quenching experiments performed at three different temperatures (288, 298 and 308 K) revealed the static mode of quenching and the binding constants (K b ∼ 106-9) obtained indicated the strong affinity of these analogs for HSA. Furthermore, significant changes in the secondary structure of HSA in the presence of these analogs were also confirmed by far UV-CD spectroscopy. The thermodynamic properties such as the enthalpy change (ΔH°), Gibbs free energy change (ΔG°) and entropy change (ΔS°) revealed that the binding process was spontaneous and exothermic. Theoretical studies, viz., DFT and molecular docking corroborated the experimental results as these five analogs could bind with HSA through hydrogen bonding and hydrophobic interactions. The present study provides useful information regarding the interaction mechanism of these analogs with HSA, which can provide a new avenue to design more potent chalcone triazole analogs for use in the biomedical field.

Design, synthesis and biological evaluation of ciprofloxacin tethered bis-1,2,3-triazole conjugates as potent antibacterial agents.

A series of new bis-1,2,3-triazole linked ciprofloxacin conjugates was designed, synthesized and evaluated in vitro antibacterial activity against a panel of clinically relevant bacteria. A significant part of the compounds displayed enhanced activity against both Gram-positive and Gram-negative species of bacteria as compared to the parent drug. Additionally, negligible toxicity profile of compounds indicates that they may act a good antibiotic in future. Despite relatively small number of synthesized conjugates, it was possible to observe important dependences between their structure and activity.

Synthesis of newer 1,2,3-triazole linked chalcone and flavone hybrid compounds and evaluation of their antimicrobial and cytotoxic activities.

The present study was carried out in an attempt to synthesize a new class of antimicrobial and antiplasmodial agents by copper catalyzed click chemistry to afford 25 compounds 10-14(a-e) of 1,4-disubstituted-1,2,3-triazole derivatives of chalcones and flavones. The structures of the newly synthesized compounds were established by elemental analysis, IR, (1)H NMR, (13)C NMR and Mass spectral data. The newly synthesized compounds were evaluated for their antibacterial activity against Gram positive bacteria (Staphylococcus aureus, Enterococcus faecalis), Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Shigella boydii, Klebsiella pneumoniae) and antifungal activity against (Candida albicans, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Dermatophyte) as well as molds (Aspergillus niger, Aspergillus fumigatus). The antiplasmodial and cytotoxic activities of these compounds were also evaluated against human malaria parasite Plasmodium falciparum strain 3D7 and human hepato-cellular carcinoma cells (Huh-7), respectively. Compounds 10a, 10c, 10d, 12c and 14e showed promising antibacterial activity while compounds 10e, 11d, 11e, 12c, 13a, 13b, 13e, 14a and 14d showed good antifungal activity as compared to the corresponding standard drugs. Compound 10b was found to be the most active against Plasmodium falciparum while the remaining compounds showed moderate to weak antiplasmodial activity. However, cytotoxic activities of all compounds were found ineffective against Huh-7 cells.