Coumaryl-sulfonamide moiety: Unraveling their synthetic strategy and specificity toward hCA IX/XII, facilitating anticancer drug development.

Currently, cancer is the most grieving threat to society. The cancer-related death rate has had an ascending trend, despite the implementation of numerous treatment strategies or the discovery of an array of potent molecules against several pathways of cancer growth. The need of the hour is to prevent the multidrug resistance toll, and the current efforts have been bestowed upon a versatile small molecule scaffold, coumarin (benz[α]pyrone), a natural compound possessing interesting affinity toward the cancer target human carbonic anhydrase (hCA), focusing on hCA I, II, IX, and XII. Along with coumarin, the age-old known antibacterial drug sulfonamide, when conjugated at positions 3, 7, and 8 of coumarin either with a linker group or as a single entity, has been reported to enhance the affinity of coumarin toward the overexpressed enzymes in tumor cell lines. The sulfonamides have been listed as obsolete drugs due to the severe side effects caused by them; however, their affinity toward the hCA-zinc-binding core has attracted the attention of researchers. Hence, in the process of drug development, coumarin and sulfonamides have remained the choice of last resort. To unveil the synthetic strategy of coumarin-sulfonamide conjugation, their rationale for inhibiting cancer cells/enzymes, and their affinity toward various types of carcinoma have been the sole goal of the researchers. This review specifically focuses on the mechanism of action and the structure-activity relationship through synthetic strategies and the binding affinity of coumaryl-sulfonamide conjugates with the anticancer targets possessing the highest enzyme affinity, since 2008.

A review on synthetic strategy, molecular pharmacology of indazole derivatives, and their future perspective.

With different nitrogen-containing heterocyclic moieties, Indazoles earn one of the places among the top investigated molecules in medicinal research. Indazole, an important fused aromatic heterocyclic system containing benzene and pyrazole ring with a chemical formula of C7 H6 N2 , is also called benzopyrazole. Indazoles consist of three tautomeric forms in which 1H-tautomers (indazoles) and 2H-tautomers (isoindazoles) exist in all phases. The tautomerism in indazoles greatly influences synthesis, reactivity, physical and even the biological properties of indazoles. The thermodynamic internal energy calculation of these tautomers points view 1H-indazole as the predominant and stable form over 2H-indazole. The natural source of indazole is limited and exists in alkaloidal nature (i.e., nigellidine, nigeglanine, nigellicine, etc.) found from Nigella plants. Some of the FDA-approved drugs like Axitinib, Entrectinib, Niraparib, Benzydamine, and Granisetron are being used to treat renal cell cancer, non-small cell lung cancer (NSCLC), epithelial ovarian cancer, chronic inflammation, chemotherapy-induced nausea, vomiting, and many more uses. Besides all these advantages regarding its biological activity, the main issue about indazoles is the less abundance in plant sources, and their synthetic derivatives also often face problems with low yield. In this review article, we discuss its chemistry, tautomerism along with their effects, different schematics for the synthesis of indazole derivatives, and their different biological activities.

Phytochemical conjugation as a potential semisynthetic approach toward reactive and reuse of obsolete sulfonamides against pathogenic bacteria.

The emergence and reemergence of multidrug-resistant (MDR) bacteria and mycobacteria in community and hospital periphery have directly enhanced the hospitalization costs, morbidity and mortality, globally. The appearance of MDR pathogens, the currently used antibiotics, remains insufficient, and the development of potent antibacterial(s) is merely slow. Thus, the development of active antibacterials is the call of the day. The sulfonamides class of antibacterials was the most successful synthesized drug in the 19th century. Mechanically, sulfonamides were targeting bacterial folic acid biosynthesis and today, those are obsolete or clinically inactive. Nevertheless, the magic sulfonamide pharmacophore has been used continuously in several mainstream antibacterial, antidiabetic, antiviral drugs. Concomitantly, thousands of phytochemicals with antimicrobial potencies have been recorded and were commanded as alternate antibacterials toward control of MDR pathogens. However, none/very few isolated phytochemicals have gone up to the pure-drug stage due to the lack of the desired drug-likeness values and the required pharmacokinetic properties. Thus, chemical modification of parent drug remains as the versatile approach in antibacterial drug development. Improvement of clinically inactive sulfa drugs with suitable phytochemicals to develop active, low-toxic drug molecules followed by medicinal chemistry could be prudent. This review highlights such "sulfonamide-phytochemical" hybrid drug development research works for utilizing inactive sulfonamides and phytochemicals; the ingenious cost-effective and resource-saving hybrid drug concept could be a new trend in current antibacterial drug discovery to reactive the obsolete antibacterials.

Molecular docking and simulation study for synthesis of alternative dapsone derivative as a newer antileprosy drug in multidrug therapy.

Leprosy (causative, Mycobacterium leprae) continues to be the persisting public health problem with stable incidence rates, owing to the emergence of dapsone resistance that being the principal drug in the ongoing multidrug therapy. Hence, to overcome the drug resistance, structural modification through medicinal chemistry was used to design newer dapsone derivative(s) (DDs), against folic acid biosynthesis pathway. The approach included theoretical modeling, molecular docking, and molecular dynamic (MD) simulation as well as binding free energy estimation for validation of newly designed seven DDs, before synthesis. Theoretical modeling, docking, and MD simulation studies were used to understand the mode of binding and efficacy of DDs against the wild-type and mutant dihydropteroate synthases (DHPS). Principal component analysis was performed to understand the conformational dynamics of DHPS-DD complexes. Furthermore, the overall stability and negative-binding free energy of DHPS-DD complexes were deciphered using Molecular Mechanics/Poisson-Boltzmann Surface Area technique. Molecular mechanics study revealed that DD3 possesses higher binding free energy than dapsone against mutant DHPS. Energetic contribution analysis portrayed that van der Waals and electrostatic energy contributes profoundly to the overall negative free energy, whereas polar solvation energy opposes the binding. Finally, DD3 was synthesized and characterized using Fourier-transform infrared spectroscopy, UV, liquid chromatography-mass spectrometry, and proton nuclear magnetic resonance techniques. This study suggested that DD3 could be further promoted as newer antileprosy agent. The principles of medicinal chemistry and bioinformatics tools help to locate effective therapeutics to minimize resources and time in current drug development modules.

Isoniazid-phytochemical conjugation: A new approach for potent and less toxic anti-TB drug development.

Mycobacterium tuberculosis (Mtb) causes one of the most grievous pandemic infectious diseases, tuberculosis (TB), with long-term morbidity and high mortality. The emergence of drug-resistant Mtb strains, and the co-infection with human immunodeficiency virus, challenges the current WHO-TB stewardship programs. The first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), have become extensively obsolete in TB control from chromosomal mutations during the last decades. However, based on clinical trial statistics, the production of well-tolerated anti-TB drug(s) is miserably low. Alternately, semi-synthesis or structural modifications of first-line obsolete antitubercular drugs remain as the versatile approach for getting some potential medicines. The use of any suitable phytochemicals with INH in a hybrid formulation could be an ideal approach for the development of potent anti-TB drug(s). The primary objective of this review was to highlight and analyze available INH-phytochemical hybrid research works. The utilization of phytochemicals through chemical conjugation is a new trend toward the development of safer/non-toxic anti-TB drugs.

Computer-aided synthesis of dapsone-phytochemical conjugates against dapsone-resistant Mycobacterium leprae.

Leprosy continues to be the belligerent public health hazard for the causation of high disability and eventual morbidity cases with stable prevalence rates, even with treatment by the on-going multidrug therapy (MDT). Today, dapsone (DDS) resistance has led to fear of leprosy in more unfortunate people of certain developing countries. Herein, DDS was chemically conjugated with five phytochemicals independently as dapsone-phytochemical conjugates (DPCs) based on azo-coupling reaction. Possible biological activities were verified with computational chemistry and quantum mechanics by molecular dynamics simulation program before chemical synthesis and spectral characterizations viz., proton-HNMR, FTIR, UV and LC-MS. The in vivo antileprosy activity was monitored using the 'mouse-foot-pad propagation method', with WHO recommended concentration 0.01% mg/kg each DPC for 12 weeks, and the host-toxicity testing of the active DPC4 was seen in cultured-human-lymphocytes in vitro. One-log bacilli cells in DDS-resistant infected mice footpads decreased by the DPC4, and no bacilli were found in the DDS-sensitive mice hind pads. Additionally, the in vitro host toxicity study also confirmed that the DCP4 up to 5,000 mg/L level was safety for oral administration, since a minor number of dead cells were found in red color under a fluorescent microscope. Several advanced bioinformatics tools could help locate the potential chemical entity, thereby reducing the time and resources required for in vitro and in vitro tests. DPC4 could be used in place of DDS in MDT, evidenced from in vivo antileprosy activity and in vitro host toxicity study.

Synthesis of novel thymol derivatives against MRSA and ESBL producing pathogenic bacteria.

Twelve substituted aryl-azo-thymol derivatives (4a to 4 l) were synthesized and characterized by several spectral techniques such as, FTIR, UV-vis, proton NMR, Mass spectrometry and elemental analysis. Antimicrobial activities were evaluated by agar-well diffusion method against isolated MRSA, ESBL-producing pathogenic bacteria and antifungal resistant fungi, in vitro. In addition, drug likeness properties of derivatives were assessed through bioinformatic tools such as, PASS prediction, molecular docking and Lipinski rules of five, along with determination of toxic nature and LD50 values. Among 12 derivatives, 4a, 4b, 4c, 4 g, 4i, 4j and 4 k had significant antibacterial and antifungal activities with minimum inhibitory concentration values, 40 to 80 µg/ml. Moreover, the docking scores of derivatives were -8.27 to -11.44 kcal/mol, against 4 bacterial targets and -9.45 to -12.49 kcal/mol against 2 fungal targets. Thus, from in vitro and in silico studies, thymol derivatives had control of MRSA, ESBL-producing bacteria and antifungal resistant fungi.

Biological investigation of novel metal complexes of 2-amino-4-substituted phenylthiazole Schiff bases.

OBJECTIVE: Invasive microorganisms and free radicals are responsible for the delayed healing of various infections. It is necessary to discovery of novel molecules that are effective against invasive microorganisms and inhibit free radicals. Therefore, a series of metal complexes of 2-amino-4-substituted phenylthiazole Schiff bases were synthesized. METHODS: Structural characterization of the synthesized molecules was performed by elemental analysis, FT/IR, 1H NMR, UV-Vis spectrophotometry, LC-MS, XRD, and SEM. The antimicrobial activities of all the synthesized molecules were investigated by an agar well diffusion method. An acute oral toxicity study of the synthesized ligands and their metal complexes was conducted according to OECD guidelines. The DPPH assay was used to evaluate the radical-scavenging activities of the compounds. RESULTS: Results of the oral acute toxicity study revealed that the synthesized analogues are safe up to a dose of 2000 mg/kg body weight. The complexes bis[{4-((4-bromo-3-methylphenyl)diazenyl)-2-((4-phenylthiazol-2-ylimino)methyl)phenoxy}]cobalt (6a) and bis[4-{(4-bromo-3-methylphenyl)diazenyl}-2-{(4-(4-chlorophenyl)thiazol-2-ylimino)methyl}phenoxy]cobalt (6d) exhibited significant antibacterial activities against drug-resistant bacterial strains as well as potent radical-scavenging properties. CONCLUSION: The results justify that the chelation of metals with Schiff base ligands enhances their biological activities against drug-resistant microbial strains.

Antimicrobial activity of novel synthesized coumarin based transitional metal complexes.

OBJECTIVES: To synthesize new transitional metal complexes derived from 3-aryl-azo-4-hydroxy coumarin analogues and to evaluate their antimicrobial activities. METHODS: The syntheses of complexes of coumarin analogues were accomplished by mixing a hydro-alcoholic solution of 3-aryl-azo-4-hydroxy coumarin analogues with transition metal chlorides. The structural environment of the synthesized molecules was characterized using different instrumental methods. The antimicrobial activity of the compounds was determined by the agar well diffusion method. RESULTS: The cobalt complexes of (E)-3-((4-chlorophenyl) diazenyl)-4-hydroxy-2H-chromen-2-one (HL1): (4a) and (E)-3-((4-methoxyphenyl) diazenyl)-4-hydroxy-2H-chromen-2-one (HL2): (4e) showed excellent antimicrobial activities compared with their ligands. CONCLUSION: The reports of the antimicrobial investigation showed that the cobalt complexes of 3-aryl-azo-4-hydroxy coumarin analogues exhibited potential antimicrobial activity that was stronger than that of their ligands.

Development of antibacterial conjugates using sulfamethoxazole with monocyclic terpenes: A systematic medicinal chemistry based computational approach.

BACKGROUND AND OBJECTIVE: To develop 6 conjugate agents of the moribund antibiotic sulfamethoxazole (SMZ) joined to 6 individual monoterpenes, followed by protocols of medicinal chemistry as potent antibacterials, against multidrug resistant (MDR) human gruesome pathogenic bacteria. METHODS: Antibacterial activities of the proposed conjugates were ascertained by the 'prediction of activity spectra of substances' (PASS) program. Drug-likeness parameters and toxicity profiles of conjugates were standardized with the Lipinski rule of five, using cheminformatic tools, Molsoft, molinspiration, OSIRIS and ProTox. Antibacterial activities of individual chemicals and conjugates were examined by targeting the bacterial folic acid biosynthesis enzyme, dihydropteroate synthases (DHPSs) of bacteria, Bacillus anthracis, Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae and Mycobacterium tuberculosis, with 3D structures of DHPSs from protein data bank. RESULTS: According to the PASS program, biological spectral values of conjugate-2, conjugate-5 and conjugate-6 were ascertained effective with 'probably active' or 'Pa' value > 0.5, for anti-infective and antituberculosic activities. Using molecular docking against 5 cited bacterial DHPSs, effective docking scores of 6 monoterpenes in the specified decreasing order (kcal/mol): -9.72 (eugenol against B. anthracis), -9.61 (eugenol against S. pneumoniae), -9. 42 (safrol, against B. anthracis), -9.39 (thymol, against M. tuberculosis), -9.34 (myristicin, against S. pneumoniae) and -9.29 (thymol, against B. anthracis); whereas the lowest docking score of SMZ was -8.46kcal/mol against S. aureus DHPS. Similarly, effective docking scores of conjugates were as specified (kcal/mol.): -10.80 (conjugate-4 consisting SMZ+safrol, against M. tuberculosis), -10.78 (conjugate-5 consisting SMZ+thymol, against M. tuberculosis), -10.60 (conjugate-5 against B. anthracis), -10.26 (conjugate-2 consisting SMZ+ eugenol, against M. tuberculosis), -10.25 (conjugate-5, against S. aureus) and -10.19 (conjugate-2 against S. pneumoniae. Conjugates-2 and -5 were the most effective antibacterials based on Lipinski rule of five with lethal doses 3471 and 3500mg/kg, respectively and toxicity class levels. CONCLUSIONS: Conjugate-2 and conjugate-5 were more effective than individual monoterpenes and SMZ, against pathogenic bacteria. Synthesis, characterization and in vitro antibacterial study with acute toxicity testing for Wister rat model of the conjugate-5 could land at success in the recorded computational trial and it could be promoted for synthesis in the control of MDR bacteria.

Antibacterial, antifungal and antimycobacterial compounds from cyanobacteria.

Infections from multidrug resistant (MDR) pathogenic bacteria, fungi and Mycobacterium tuberculosis remain progressively intractable. The search of effective antimicrobials from other possible non-conventional sources against MDR pathogenic bacteria, fungi and mycobacteria is call of the day. This review considers 121 cyanobacterial compounds or cyano-compounds with antimicrobial activities. Chemical structures of cyano-compounds were retrieved from ChemSpider and PubChem databases and were visualized by the software ChemDraw Ultra. Chemical information on cyano-compounds pertaining to Lipinski rules of five was assessed. The reviewed cyano-compounds belong to the following chemical classes (with examples): alkaloids (ambiguine isonitriles and 12-epi-hapalindole E isonitrile), aromatic compounds (benzoic acid and cyanobacterin), cyclic depsipeptides (cryptophycin 52 and lyngbyabellin A), cyclic peptides (calophycin and tenuecyclamides), cyclic undecapeptides (kawaguchipeptins and lyngbyazothrin A), cyclophane (carbamidocyclophane), extracellular pigment (nostocine A), fatty acids (alpha-dimorphecolic acid and majusculonic acid), linear peptides (muscoride A), lipopeptides (fischerellins and scytonemin A), nucleosides (tolytoxin and tubercidin), phenols (ambigols and 4-4'-hydroxybiphenyl), macrolides (scytophycin A and tolytoxin), polyketides (malyngolide and nostocyclyne), polyphenyl ethers (crossbyanol A), porphinoids (tolyporphin J) and terpenoids (noscomin and scytoscalarol). Cyanobacteria appear to be a diverse source of compounds with antimicrobial activity. Further attention is required to elucidate whether those could be applied as pharmaceuticals.

Antibacterial activity, computational analysis and host toxicity study of thymol-sulfonamide conjugates.

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus faecalis (VRE) are notorious pathogenic multidrug resistant (MDR) bacteria in both hospital and community sectors, and today the first antibacterial drug sulfamethoxazole is ineffective. The monoterpene phenol, thymol was conjugated with seven sulfa drug derivatives individually, adopting the dye-azo synthesis protocol, and conjugates were characterized using spectral analysis techniques such as, UV, FTIR, MS, HPLC, 1H NMR, 13C NMR and SEM. Conjugates were assessed for antibacterial activity in vitro and in silico; the zone of inhibition, MIC and MBC values of each conjugate were determined against isolated MRSA and VRE strains from clinical samples. As 3-dimentional structures of dihydropteroate synthases (DHPSs) of targeted bacteria are not available in protein database, homology models of DHPS enzymes of both bacteria were generated and validated by Ramachandran plots. Seven conjugates were used as ligands in molecular docking against MRSA-DHPS and VRE-DHPS. Additionally bioinformatics tools, PASS prediction, Lipinski rules of five, computational LD50 value, toxicity class, HOMO, LUMO and EPS plots were carried out to assess standard drug-likeliness properties of conjugates. Zone size inhibition of the conjugate, 4b (thymol+sulfadiazine) against MRSA and VRE strains on agar plates were 20 and 40µg/mL as the lowest MIC and MBC values, respectively; while the reference antibiotic ampicillin had the lowest MIC and MBC values at 80 to 180µg/mL. In vitro host-toxicity testing was carried out with cultured human-lymphocytes from umbilical cord blood, and 4b was broadly non-toxic to human cells at 15,000mg/L. Thus, 4b could be promoted a newer antibacterial, against gruesome MDR bacteria.