Synthesis and biological evaluation of new naphthalimide-thiourea derivatives as potent antimicrobial agents active against multidrug-resistant Staphylococcus aureus and Mycobacterium tuberculosis.

The emergence of antibiotic resistance to S. aureus and M. tuberculosis, particularly MRSA, VRSA, and drug-resistant tuberculosis, poses a serious threat to human health. Towards discovering new antibacterial agents, we designed and synthesized a series of new naphthalimide-thiourea derivatives and evaluated them against a panel of bacterial strains consisting of E. coli, S. aureus, K. pneumoniae, P. aeruginosa, A. baumannii and various mycobacterial pathogens. Compounds 4a, 4l, 4m, 4n, 4q, 9f, 9l, 13a, 13d, 13e, 17a, 17b, 17c, 17d, and 17e demonstrated potent antibacterial activity against S. aureus with MIC 0.03-8 µg mL-1. In addition, these compounds have also exhibited potent inhibition against MDR strains of S. aureus, including VRSA with MICs 0.06-4 µg mL-1. Compounds 4h, 4j, 4l, 4m, 4q, 4r, 9a, 9b, 9c, 9d, 9e, 9g, 9h, 9j, 13f and 17e also exhibited good antimycobacterial activity against M. tuberculosis with MIC 2-64 µg mL-1. The cytotoxicity assay using Vero cells revealed that all the compounds were non-toxic and exhibited a favorable selectivity index (SI >40). Time kill kinetics data indicated that compounds exhibited concentration-dependent killing. Furthermore, in silico studies were performed to decipher the possible mechanism of action. Comprehensively, these results highlight the potential of naphthalimide-thiourea derivatives as promising antibacterial agents.

Development of venetoclax with 2-hydroxypropyl-beta-cyclodextrin inclusion complex for improved bioavailability.

Cyclodextrin complexes loaded with venetoclax for improved solubility and therapeutic efficacy as repurposed drug. The venetoclax-cyclodextrin inclusion complex was prepared using kneading method. Primarily in-silico molecular docking study was performed to examine the possible interaction between venetoclax and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and extensively characterized. The in-vitro studies were performed using A-549 lung epithelial cancer cells. The in-vivo pharmaco-kinetic studies was performed on wistar rats. The aqueous solubility of venetoclax was increased upto 3.16 folds, as compared with pure venetoclax with entrapment efficiency (EE%) was determined 95.44 ± 0.3%. In-vitro cytotoxicity studies were carried on A-549 lung epithelial cancer cells, wherein BCL-2 receptors were highly over-expressed and IC 50 values for venetoclax and venetoclax- HP-ß-CD complex was calculated at 24 and 48 hrs in the order of 1.241 µg/ml, 0.68 µg/ml and 0.757719 µg/ml, 0.6125 µg/mL, respectively. The oral bioavailability was increased 4.03 times compared to the pure drug. The venetoclax-HP-ß-CD inclusion complexes showed the increased aqueous solubility with improved anticancer activities.Communicated by Ramaswamy H. Sarma.

Synthesis and antibacterial evaluation of (E)-1-(1H-indol-3-yl) ethanone O-benzyl oxime derivatives against MRSA and VRSA strains.

Infections caused due to multidrug resistant organisms have emerged as a constant menace to human health. Even though numerous antibiotics are currently available for treating infectious diseases, a great number of bacterial strains have acquired resistance to many of them. Among these, infections caused due to Staphylococcus aureus are predominant in adult and paediatric population. Indole is a prominent chemical scaffold found in many pharmacologically active natural products and synthetic drugs. A number of oxime ether containing compounds have attracted attention of researchers owing to their interesting biological properties. Current work details the synthesis of indole containing oxime ether derivatives and their evaluation for antimicrobial activity against a panel of bacterial and mycobacterial strains. Synthesized compounds demonstrated good to moderate activity against drug-resistant S. aureus including resistant to vancomycin. Among all, compound 5h was found to possess potent activity against susceptible as well as MRSA and VRSA strains of S. aureus with MIC of 1 µg/mL and 2-4 µg/mL respectively. In addition, compound 5h was found to be non-toxic to Vero cells and exhibited good selectivity index of >40. Further, 5h, E-9a and E-9b possessed good biofilm inhibition against S. aureus. With these assuring biological properties, synthesized compounds could be potential prospective antimicrobial agents.

Fused-azepinones: Emerging scaffolds of medicinal importance.

Hymenialdisine an alkaloid of oroidin class has drawn the attention of researchers owing to its unique structural features and interesting biological properties. Hymenialdisine exhibited promising inhibitory activity against a number of therapeutically important kinases viz., CDKs, GSK-3ß etc., and showed anti-cancer, anti-inflammatory, anti-HIV, neuroprotective, anti-fouling, anti-plasmodium properties. Hymenialdisine and other structurally related oroidin alkaloids such as dibromo-hymenialdisine, stevensine, hymenin, axinohydantoin, spongicidines A-D, latonduines and callyspongisines contain pyrrolo[2,3-c] azepin-8-one core in common. Keeping in view of the interesting structural and therapeutic features of HMD, several structural modifications were carried around the fused-azepinone core which resulted in a number of diverse structural motifs like indolo-azepinones, paullones, aza-paullones, darpones and 5,7-dihydro-6H-benzo[b]pyrimido[4,5-d] azepin-6-one. In this review, an attempt is made to collate and review the structures of diverse hymenialdisine and related fused-azepinones of synthetic/natural origin and their biological properties.

A microwave-assisted copper-mediated tandem approach for fused quinazoline derivatives.

A method for the microwave-assisted copper-mediated oxidative coupling reaction of different aldehydes and quinazolines/benzimidazoles has been developed for the synthesis of fused-polycyclic systems via new C-N bond formation. The current methodology involves the use of environmentally benign NH4OAc as the amine source in the presence of 2-propanol as the solvent. This novel tandem reaction approach offers a rapid and straightforward access to complex fused quinazoline derivatives in an efficient manner.

Synthesis and evaluation of new quinazoline-benzimidazole hybrids as potent anti-microbial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis.

Owing to the rapid rise in antibiotic resistance, infectious diseases have become serious threat to public health. There is an urgent need to develop new antimicrobial agents with diverse chemical structures and novel mechanisms of action to overcome the resistance. In recent years, Quinazoline-benzimidazole hybrids have emerged as a new class of antimicrobial agents active against S. aureus and M. tuberculosis. In the current study, we designed and synthesized fifteen new Quinazoline-benzimidazole hybrids and evaluated them for their antimicrobial activity against S. aureus ATCC 29213 and M. tuberculosis H37Rv. These studies led to the identification of nine potent antibacterial agents 8a, 8b, 8c, 8d, 8f, 8g, 8h, 8i and 10c with MICs in the range of 4-64 µg/mL. Further, these selected compounds were found to possess potent antibacterial potential against a panel of drug-resistant clinical isolates which include methicillin and vancomycin-resistant S. aureus. The selected compounds were found to be less toxic to Vero cells (CC50 = 40-≥200 µg/mL) and demonstrated a favourable selectivity index. Based on the encouraging results obtained these new benzimidazol-2-yl quinazoline derivatives have emerged as promising antimicrobial agents for the treatment of MDR- S. aureus and Mycobacterial infections.

FabI (enoyl acyl carrier protein reductase) - A potential broad spectrum therapeutic target and its inhibitors.

Development of new anti-bacterial agents acting upon underexploited targets and thus evading known mechanisms of resistance is the need of the hour. The highly conserved and distinct bacterial fatty acid biosynthesis pathway (FAS-II), presents a validated and yet relatively underexploited target for drug discovery. FabI and its isoforms (FabL, FabK, FabV and InhA) are essential enoyl-ACP reductases present in several microorganisms. In addition, the components of the FAS-II pathway are distinct from the multi-enzyme FAS-I complex found in mammals. Thus, inhibition of FabI and its isoforms is anticipated to result in broad-spectrum antibacterial activity. Several research groups from industry and academic laboratories have devoted significant efforts to develop effective FabI-targeting antibiotics, which are currently in various stages of clinical development for the treatment of multi-drug resistant bacterial infections. This review summarizes all the natural as well as synthetic inhibitors of gram-positive and gram-negative enoyl ACP reductases (FabI). The knowledge of the reported inhibitors can aid in the development of broad-spectrum antibacterials specifically targeting FabI enzymes from S. aureus, S. epidermidis, B. anthracis, B. cereus, E. coli, P. aeruginosa, P. falciparum and M. tuberculosis.

Copper mediated one-pot synthesis of quinazolinones and exploration of piperazine linked quinazoline derivatives as anti-mycobacterial agents.

A facile method was developed for the synthesis of quinazolinone derivatives in a one-pot condensation reaction via in situ amine generation using ammonia as the amine source and with the formation of four new C-N bonds in good to excellent yields. With the optimised method, we synthesized a library of piperazine linked quinazoline derivatives and the synthesized compounds were evaluated for their inhibitory activity against Mycobacterium tuberculosis. The compounds 8b, 8e, 8f, 8m, 8n and 8v showed potent anti-mycobacterial activity with MIC values of 2-16 µg mL-1. All the synthesized compounds follow Lipinski's rules for drug likeness.

Facile synthesis of 1,2,3-triazole-fused indolo- and pyrrolo[1,4]diazepines, DNA-binding and evaluation of their anticancer activity.

A facile synthetic strategy has been developed for the generation of structurally diverse N-fused heterocycles. The formation of fused 1,2,3-triazole indolo and pyrrolodiazepines proceeds through an initial Knoevenagel condensation followed by intramolecular azide-alkyne cycloaddition reaction at room temperature without recourse to the traditional Cu(I)-catalyzed azide-alkyne cycloadditions. The synthesized compounds were evaluated for their in vitro anti-cancer activity against the NCI 60 cell line panel. Among the tested compounds, 3a and 3h were found to exhibit potent inhibitory activity against many of the cell lines. Cell cycle analysis indicated that the compounds inhibit the cell cycle at sub G1 phase. The DNA- nano drop method, viscosity experiment and docking studies suggested these compounds possess DNA binding affinity.

Promising antibacterial agents against multidrug resistant Staphylococcus aureus.

Rapid emergence of multidrug resistant Staphylococcus aureus infections has created a critical health menace universally. Resistance to all the available chemotherapeutics has been on rise which led to WHO to stratify Staphylococcus aureus as high tier priorty II pathogen. Hence, discovery and development of new antibacterial agents with new mode of action is crucial to address the multidrug resistant Staphylococcus aureus infections. The egressing understanding of new antibacterials on their biological target provides opportunities for new therapeutic agents. This review underlines on various aspects of drug design, structure activity relationships (SARs) and mechanism of action of various new antibacterial agents and also covers the recent reports on new antibacterial agents with potent activity against multidrug resistant Staphylococcus aureus. This review provides attention on in vitro and in vivo pharmacological activities of new antibacterial agents in the point of view of drug discovery and development.

Cinnamamide: An insight into the pharmacological advances and structure-activity relationships.

The cinnamamide (cinnamic acid amide and cinnamide) is a privileged scaffold present widely in a number of natural products. The scaffold acts as a useful template for designing and arriving at newly drug-like molecules with potential pharmacological activity. An attempt has been made to review the extensive occurrence of cinnamamide scaffold in many lead compounds reported for treating various diseases, their binding interactions with the therapeutic targets as well as mechanism of action and their structure-activity relationships. The discoveries of cinnamamide systems and some examples of unusual cinnamamides having an aromatic, aliphatic, and heterocyclic or other rings condensed to the basic cinnamamide structure also have been extensively covered in this review.

Synthesis and evaluation of new quinazolin-4(3H)-one derivatives as potent antibacterial agents against multidrug resistant Staphylococcus aureus and Mycobacterium tuberculosis.

Staphylococcus aureus and Mycobacterium tuberculosis are major causative agents responsible for serious nosocomial and community-acquired infections impacting healthcare systems globally. Over several decades, these pathogens have developed resistance to multiple antibiotics significantly affecting morbidity and mortality. Thus, these recalcitrant pathogens are amongst the most formidable microbial pathogens for which international healthcare agencies have mandated active identification and development of new antibacterial agents for chemotherapeutic intervention. In our present work, a series of new quinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP pathogens and pathogenic mycobacteria. The experiments revealed that 4'c, 4'e, 4'f and 4'h displayed selective and potent inhibitory activity against Staphylococcus aureus with MIC values ranging from 0.03-0.25 µg/mL. Furthermore, compounds 4'c and 4'e were found to be benign to Vero cells (CC50 = >5 µg/mL) and displayed promising selectivity index (SI) > 167 and > 83.4 respectively. Additionally, 4'c and 4'e demonstrated equipotent MIC against multiple drug-resistant strains of S. aureus including VRSA, concentration dependent bactericidal activity against S. aureus and synergized with FDA approved drugs. Moreover, compound 4'c exhibited more potent activity in reducing the biofilm and exhibited a PAE of ∼2 h at 10X MIC which is comparable to levofloxacin and vancomycin. In vivo efficacy of 4'c in murine neutropenic thigh infection model revealed that 4'c caused a similar reduction in cfu as vancomycin. Gratifyingly, compounds 4d, 4e, 9a, 9b, 14a, 4'e and 4'f also exhibited anti-mycobacterial activity with MIC values in the range of 2-16 µg/mL. In addition, the compounds were found to be less toxic to Vero cells (CC50 = 12.5->100 µg/mL), thus displaying a favourable selectivity index. The interesting results obtained here suggest the potential utilization of these new quinazolin-4(3H)-one derivatives as promising antibacterial agents for treating MDR-Staphylococcal and mycobacterial infections.

Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health.

Adenosine 5'-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.

Synthesis and evaluation of new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives as potent antibacterial agents effective against multidrug resistant Staphylococcus aureus.

Treatment of nosocomial and community acquired Staphylococcus aureus infections has become more challenging due to the egression of multi-drug resistance. This has spurred the need for rapid development of new therapeutic agents which can effectively negate the resistance mechanisms. In our current work, several new 4-oxoquinazolin-3(4H)-yl)benzoic acid and benzamide derivatives were synthesized and examined for their antimicrobial activity against ESKAP pathogen panel and pathogenic mycobacteria. In the primary screening, compounds 4a, 4b, 6'a, 6'b, 6'h, 6'i and 6'j were found to demonstrate selective and potent inhibitory activity against Staphylococcus aureus (MICs = 0.25-0.5 µg/mL). When tested against Vero cells, all the compounds were found to be non toxic possessing favourable selectivity index (SI > 10), which encouraged us for carrying out further studies. Compound 6'a (SI > 40) was tested against a number of multiple clinical strains of multi-drug resistant S. aureus and was found to exhibit potent activity, irrespective of the resistant status of the strain. Besides, compound 6'a also exhibited concentration dependent bactericidal activity and synergized with the FDA approved drugs tested. The interesting results obtained suggest the potential utility of the newly synthesized compounds for treatment of multidrug resistant S. aureus infections.

Synthesis of 1,2,3-triazole linked 4(3H)-Quinazolinones as potent antibacterial agents against multidrug-resistant Staphylococcus aureus.

Methicillin and vancomycin resistant Staphylococcus aureus infections are an emerging global health concern leading to increasing morbidity and mortality. Continuous increase in drug resistance has underlined the need for discovery and development of new antibacterial agents acting via novel mechanisms to overcome this pressing issue. In this context, a number of 1,2,3-triazole linked 4(3H)-quinazolinone derivatives were designed and synthesized as potent antibacterial agents. When evaluated against ESKAP pathogen panel, compounds 7a, 7b, 7c, 7e, 7f, 7g, 7h, 7i, 9a, 9c, 9d and 9e exhibited significantly selective inhibitory activities towards Staphylococcus aureus (MIC = 0.5-4 µg/mL). To understand and confirm the specificity of these compounds, the compounds 7a and 9a were tested against E. coli and A. baumannii in combination with sub-lethal concentrations of Polymyxin B nonapeptide (PMBN) and were found to be inactive. This clearly indicated that these compounds possess specific and potent activity towards S. aureus and are inactive against gram-negative pathogens. Encouragingly, the compounds were also found to be non toxic to Vero cells and displayed favourable selectivity index (SI = 40 to 80). Furthermore, 7a and 9a were found to possess potent inhibitory activity when tested against multidrug resistant S. aureus including strains resistant to vancomycin (MIC values 0.5-32 µg/mL), indicating that the compounds are able to escape current drug-resistance mechanisms. With the potent anti-bacterial activity exhibited the new series of 1,2,3-triazole linked 4(3H)-quinazolinones have emerged as promising candidates for treating multidrug resistant Staphylococcus aureus infections.

Synthesis of new 3-phenylquinazolin-4(3H)-one derivatives as potent antibacterial agents effective against methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA).

Occurrence of infections due to the drug resistant Staphylococcus aureus is on rise necessitating the need for rapid development of new antibacterial agents. In our present work, a series of new 3-phenylquinazolin-4(3H)-one derivatives were designed, synthesized and evaluated for their antibacterial activity against ESKAP (E. coli, S. aureus, K. pneumoniae, A. baumannii, P. aeroginosa) pathogen panel and pathogenic mycobacterial strains. The study revealed that compounds 4a, 4c, 4e, 4f, 4g, 4i, 4o and 4p exhibited selective and potent inhibitory activity against Staphylococcus aureus with MIC values in the range of 0.125-8 µg/mL. Further, the compounds 4c, 4e and 4g were found to be non toxic to Vero cells (CC50 = >10->100 µg/mL) and exhibited favourable selectivity index (SI = 40->200). The compounds 4c, 4e and 4g also showed potent inhibitory activity against various MDR-S. aureus including VRSA. The promising results obtained indicated the potential use of the above series of compounds as promising antibacterial agents for the treatment of multidrug resistant Staphylococcus aureus infections.