Benzo[d]thiazole-2-carboxamides as new antituberculosis chemotypes inhibiting mycobacterial ATP phosphoribosyl transferase.

Aims: The screening of antimycobacterial benzo[d]thiazole-2-carboxamides against ATP-phosphoribosyl transferase (ATP-PRTase) was conducted. Materials & methods: The antitubercular potential of compounds 1 and 2 against ATP-PRTase was assessed through the determination of half maximal effective concentration (EC50) and binding constant (Kd), as well as competitive inhibitory studies and studies of perturbation of secondary structure, molecular modeling and L-histidine complementation assay. Results & conclusion: Compounds 1n and 2a significantly inhibited ATP-PRTase as evidenced by their EC50 and Kd values and the perturbation of the secondary structure study. Compound 1n exhibited stronger competitive inhibition toward ATP compared with 2a. The inhibition of the growth of Mycobacterium tuberculosis by targeting the L-histidine biosynthesis pathway and molecular modeling studies further supported the inhibition of ATP-PRTase.

Bacterial FtsZ inhibition by benzo[d]imidazole-2-carboxamide derivative with anti-TB activity.

Aims: The present study aimed to assess the mode of action of previously reported anti-Mycobacterium tuberculosis benzo[d]imidazole-2-carboxamides against FtsZ along with their antibacterial potential. Materials & methods: The anti-mycobacterial action of benzo[d]imidazole-2-carboxamides against FtsZ was evaluated using inhibition of Bacillus subtilis 168, light scattering assay, circular dichroism spectroscopy, in silico molecular docking and molecular dynamics simulations. Results & conclusion: Three compounds (1k, 1o and 1e) were active against isoniazid-resistant strains. Four compounds (1h, 1i, 1o and 4h) showed >70% inhibition against B. subtilis 168. Compound 1o was the most potent inhibitor (91 ± 5% inhibition) of B. subtilis 168 FtsZ and perturbed its secondary structure. Molecular docking and molecular dynamics simulation of complexed 1o suggested M. tuberculosis FtsZ as a possible target for antitubercular activity.

Domino synthesis of functionalized pyridine carboxylates under gallium catalysis: Unravelling the reaction pathway and the role of the nitrogen source counter anion.

The catalytic potential of various metal Lewis acid catalysts have been assessed to derive a high-yielding, multi-component domino synthesis of functionalized pyridines from (E)-3-(dimethylamino)-1-aryl/heteroaryl-prop-2-en-1-ones, 1,3-dicarbonyl compounds, and an ammonium salt (as the nitrogen precursor). Amongst the various metal halides, tetrafluoroborates, perchlorates, and triflates used as the catalyst, GaI3 proved to be the most effective. The mechanistic course of the most plausible pathway has been outlined as the intermediate formation of imine/enamine by the reaction of the 1,3-dicarbonyl compound with ammonia (liberated in situ from the ammonium salt used as the nitrogen source), which participates in the domino nucleophilic Michael reaction to the (2E)-3-(dimethylamino)-1-aryl/hetroarylprop-2-en-1-one by its active methylene carbon through its enamine form followed by intramolecular cyclization and aromatization. The effect of different ammonium salts as the nitrogen source has been investigated and NH4 OAc was found to be best. The influence of the acetate counter anion of NH4 OAc on the progress of the reaction was studied and its specific role in the cyclization and subsequent aromatization has been revealed. This work offers distinct advantages compared to the literature reported methodologies on the count of several green index parameters.

Design, synthesis, and biological evaluation of benzo[d]imidazole-2-carboxamides as new anti-TB agents.

Tuberculosis is the leading cause of death globally among infectious diseases. Due to the development of resistance of Mycobacterium tuberculosis to currently used anti-TB medicines and the TB-HIV synergism the urgent need to develop novel anti-mycobacterial agents has been realized. The drug-to-target path has been the successful strategy for new anti-TB drug development. All the six drug candidates that have shown promise during the clinical trials and some of these being approved for treatment against MDR TB are the results of phenotype screening of small molecule compound libraries. In search of compounds belonging to novel pharmacophoric class that could be subjected to whole cell assay to generate new anti-TB leads the benzo[d]imidazole-2-carboxamide moiety has been designed as a novel anti-TB scaffold. The design was based on the identification of the benzimidazole ring as a prominent substructure of the FDA approved drugs, the structural analysis of reported anti-TB benzimidazoles, and the presence of the C-2 carboxamido functionality in novel bioisoteric anti-TB benzothiazoles. Twenty seven final compounds have been prepared via NH4Cl-catalyzed amidation of ethyl benzo[d]imidazole-2-carboxylates, as the required intermediates, obtained through a green "all water" one-pot synthetic route following a tandem N-arylation-reduction-cyclocondensation procedure. All of the synthesised target compounds were assessed for anti-TB potential using H37Rv ATCC27294 strain. Thirteen compounds were found with better MIC (0.78-6.25 µg/mL) than the standard drugs and being non-cytotoxic nature (<50% inhibition against RAW 264.7 cell lines at 50 µg/mL). The compound 8e exhibited best anti-TB activity (MIC: 2.15 µM and selectivity index: > 60) and a few others e.g., 8a, 8f, 8k and 8o are the next best anti-TB hits (MIC: 1.56 µg/mL). The determination and analysis of various physiochemical parameters revealed favorable druglike properties of the active compounds. The compounds 8a-l and 8o, with MIC values of ≤ 6.25 µg/mL, have high LipE values (10.66-11.77) that are higher than that of the suggested value of > 6 derived from empirical evidence for quality drug candidates and highlight their therapeutic potential. The highest LipE value of 11.77 of the best active compound 8e with the MIC of 0.78 µg/mL indicates its better absorption and clearance as a probable clinical candidate for anti-TB drug discovery. These findings highlight the discovery of benzimidazole-2-carboxamides for further development as new anti-TB agents.

Ruthenium (II) Catalyzed C(sp2 )-H Bond Alkenylation of 2-Arylbenzo[d]oxazole and 2-Arylbenzo[d]thiazole with Unactivated Olefins.

Functionalization of the bio-relevant heterocycles 2-arylbenzo[d]oxazole and 2-arylbenzo[d]thiazole has been achieved through Ru(II)-catalyzed alkenylation with unactivated olefins leading to selective formation of the mono-alkenylated products. This approach has a broad substrate scope with respect to the coupling partners, affords high yields, and works for gram scale synthesis using a readily available Ru-based catalyst. Mechanistic studies reveal a C-H activation pathway for the dehydrogenative coupling leading to the alkenylation. However, the results of the ESI-MS-guided deuterium kinetic isotope effect studies indicate that the C-H activation stage may not be the rate-determining step of the reaction. The use of a radical scavenging agent such as TEMPO did not show any detrimental effect on the reaction outcome, eliminating the possibility of the involvement of a free-radical pathway.

Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation.

In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis H37Rv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4-6.25 µg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (<30% inhibition at 50 µg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 µg/mL] and the compound 6d [MIC (H37Rv) of 0.78 µg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 µg/mL, respectively.

Characterization of Photodegradation Products of Bepotastine Besilate and In Silico Evaluation of Their Physicochemical, Absorption, Distribution, Metabolism, Excretion and Toxicity Properties.

Bepotastine (BPT) is a H1-receptor antagonist. It is used as a besilate salt in ophthalmic solution for allergic conjunctivitis and orally for the treatment of allergic rhinitis and urticaria/pruritus. Its systematic forced degradation study is unreported. The same was carried out in different conditions prescribed by International Conference on Harmonisation. The stressed solutions were subjected to reversed phase liquid chromatographic analysis, and BPT was observed to be labile under photobasic condition only, yielding 5 photodegradation products. The structures of the latter were elucidated from data generated by liquid chromatography-high-resolution mass spectrometry and multistage mass spectrometry. Of the 5, 4 products were further isolated and subjected to nuclear magnetic resonance spectroscopy to justify the proposed structures. Two of them, with similar accurate mass, were additionally and unambiguously characterized from their heteronuclear multiple bond correlation data, hydrogen deuterium exchange mass data, and quantum chemical analysis using density functional theory calculations. One degradation product had a structure that could only be explained by unusual rearrangement involving conversions of N-oxide into hydroxylamine, similar to Meisenheimer rearrangement. The physicochemical, as well as absorption, distribution, metabolism, excretion, and toxicity properties of BPT and its characterized photodegradation products were evaluated in silico by ADMET Predictor™ software.

Cyclic enaminone as new chemotype for selective cyclooxygenase-2 inhibitory, anti-inflammatory, and analgesic activities.

The cyclic enaminone moiety has been identified as a new scaffold for selective inhibition of cyclooxygenase-2 with anti-inflammatory and analgesic activities. The designed cyclic enaminones have been synthesized conveniently through the development of a new catalyst-free methodology and evaluated for cyclooxygenase (COX-1 and COX-2) inhibitory activities. Three compounds 7d, 8, and 9 predominantly inhibited COX-2 with selectivity index of 74.09, 19.45 and 108.68, respectively, and were assessed for in vivo anti-inflammatory activity in carrageenan induced rat paw edema assay. The anti-inflammatory activity of 7d was comparable to that of celecoxib at a dose of 12.5 mg/kg. However, the compounds 8 and 9 were more/equally effective as anti-inflammatory agent compared to celecoxib at the doses of 12.5 mg/kg and 25 mg/kg and also exhibited anti-inflammatory activity comparable to that of diclofenac. The therapeutic potential of the most active compound 9 was further assessed by performing in vivo thermal and mechanical hyperalgesia tests using various models that revealed its analgesic activity. The in vivo non-ulcerogenicity of 9 revealed the gastrointestinal safety as compared to the non-selective COX inhibitor indomethacin. The in vitro antioxidant activity and in vivo experiments on heart rate and blood pressure provided the cardiovascular safety profile of 9. The molecular docking studies rationalize the COX-2 selectivity of the newly found anti-inflammatory compounds 7d, 8, and 9.

An unprecedented intramolecular to intermolecular mechanistic switch in 1,1-diaminoazines leading to differential product formation during the I2-induced tandem oxidative transformation.

The tautomeric preference of guanylhydrazones towards the azine form induces an unprecedented intramolecular to intermolecular mechanistic switch during the I2-catalyzed oxidative transformation leading to 4,5-disubstituted-3-amino-1,2,4-triazoles in contrast to the reaction of semicarbazones and thiosemicarbazones to form 1,3,4-oxa/thiadiazoles. This intramolecular to intermolecular cyclization shift was established through control experiments and was attributed to the high energy demand (∼22 kcal mol-1) for the azine tautomer to adopt the s-cis conformation which is essential for the intramolecular reaction. An I2 induced protocol for an efficient and straightforward synthesis of 4,5-disubstituted-3-amino-1,2,4-triazoles has been developed via tandem oxidative transformation of guanylhydrazones (in its preferentially existing azine tautomeric form) with distinct advantages such as wide substrate scope, use of substoichiometric amounts of iodine, no requirement of external oxidizing agents, base free reaction conditions, short reaction time and moderate to good yields. The role of silver salt in improving the yield and shortening of reaction time was also highlighted.

α-Sulfonamidophosphonates as new anti-mycobacterial chemotypes: Design, development of synthetic methodology, and biological evaluation.

Tuberculosis (TB) is the leading cause of death worldwide due to bacterial infection. The scarcity of effective drugs to treat the disease and the compounded problems due to the development of resistance to the available therapeutics and TB-HIV synergism drive medicinal chemists to search for new anti-Mtb chemotypes. Towards this endeavor, the α-sulfonamidophosphonate moiety has been identified as new anti-Mtb chemotype through the scaffold hopping as the design strategy, development of an effective synthetic methodology using green chemistry tools, and evaluation of anti-TB activity of the synthesized compounds against Mtb (Mycobacterium tuberculosis) H37Rv. Out of the sixteen compounds, five have been found to have MIC values of 1.56 µg/mL and one 3.125 µg/mL. The five most active compounds are non-cytotoxic to RAW 264.7 (mouse leukemic monocyte macrophage) cell lines. The compounds are found to possess acceptable values of the various parameters for drug likeness in accordance with the Lipinski rule with the topological surface area (tPSA) of >70 that suggest eligibility of these new molecular entities for further consideration as potential drug candidates.

Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis, biological evaluation, and structure-activity relationship.

Tuberculosis is the second leading cause of deaths worldwide. The inadequacy of existing drugs to treat TB due to developed resistance and TB-HIV synergism urges for new anti-TB drugs. Seventy-two benzo[d]thiazole-2-carbanilides have been synthesized through CDI-mediated direct coupling of benzo[d]thiazole-2-carboxylic acids with aromatic amines using a three step methodology which includes a green protocol for synthesis of ethyl benzo[d]thiazole-2-carboxylates, precursor of the desired carboxylic acids. The compounds were evaluated in vitro for anti-tubercular activity against M. tuberculosis H37Rv (ATCC27294 strain). Thirty-two compounds exhibiting MIC values in the range of 0.78-6.25 µg/mL (1.9-23 µM) were subjected to cell viability test against RAW 264.7 cell lines and thirty compounds were found to be non-toxic (<50% inhibition). The most active compounds with MIC of 0.78 µg/mL (e.g., 4i, 4n, 4s, 4w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w) exhibit therapeutic index of 64. The structure activity relationship of the N-arylbenzo[d]thiazole-2-carboxamides has been established for anti-mycobacterial activity. Molecular docking suggests that the compounds 7w, 4i and 4n bind to the catalytic site of the enzyme ATP Phosphoribosyltransferase (HisG) and might be attributed to their anti-TB potential. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.

Study of degradation behaviour of montelukast sodium and its marketed formulation in oxidative and accelerated test conditions and prediction of physicochemical and ADMET properties of its degradation products using ADMET Predictor™.

Study of oxidative stability of pharmaceutical actives and formulations is important as oxidation pathway is the second most significant route for the decay of pharmaceuticals. Montelukast sodium, a leukotriene receptor antagonist, is prone to oxidation reactions owing to sensitive moieties in its structure. It is also known to be light sensitive. This study was aimed to understand the degradation behaviour of the drug in different oxidative media containing hydrogen peroxide, AIBN, Fe3+, Fenton's reagent and O2 environment under normal laboratory light conditions. The degradation behaviour of the drug was also evaluated in solid sate under ICH recommended accelerated stability condition of 40 °C/75% RH to correlate with the degradation products (DPs) formed in a solid oral formulation. A total of nine DPs (MTK 1 to MTK 9) were formed from both the drug substance and the marketed tablet formulation on storage under controlled oxygen environment in normal laboratory light and temperature conditions. These DPs were well separated on a C-18 column using a gradient HPLC method. The characterization of DPs was done based on HRMS and multi-stage tandem mass spectrometric (MSn) data. The knowledge of the structure of DPs helped in laying down degradation pathway of the drug. Also, mechanism for the formation of each DP was postulated. Finally, physicochemical as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the DPs were predicted by ADMET Predictor™ software.

Can Remote N-Heterocyclic Carbenes Coordinate with Main Group Elements? Synthesis, Structure, and Quantum Chemical Analysis of N+ -Centered Complexes.

Remote N-heterocyclic carbenes (rNHCs), such as N-methyl-4-pyridylidene, are known to form coordination complexes with TMs. Herein, it is established that rNHCs can also coordinate to the N+ centre. Synthesis of some novel divalent NI complexes with the general formula (rNHC)→N+ ←(NHC) and (rNHC)→N+ ←(rNHC) was achieved, and X-ray diffraction studies supported the coordination bond character between the rNHCs and the N+ centre. Quantum chemical analysis established the presence of divalent NI character at the central nitrogen in these systems.

Rationalization of Benzazole-2-carboxylate versus Benzazine-3-one/Benzazine-2,3-dione Selectivity Switch during Cyclocondensation of 2-Aminothiophenols/Phenols/Anilines with 1,2-Biselectrophiles in Aqueous Medium.

The cyclocondensation reaction of 2-aminothiophenols with 1,2-biselectrophiles such as ethyl glyoxalate and diethyl oxalate in aqueous medium leads to the formation of benzothiazole-2-carboxylates via the 5-endo-trig process contrary to Baldwin's rule. On the other hand, the reaction of 2-aminophenols/anilines produced the corresponding benzazine-3-ones or benzazine-2,3-diones via the 6-exo-trig process in compliance with Baldwin's rule. The mechanistic insights of these cyclocondensation reactions using the hard-soft acid-base principle, quantum chemical calculations (density functional theory), and orbital interaction studies rationalize the selectivity switch of benzothiazole-2-carboxylates versus benzazine-3-ones/benzazine-2,3-diones. The presence of water facilitates these cyclocondensation reactions by lowering of the energy barrier.

Guanylthiourea derivatives as potential antimalarial agents: Synthesis, in vivo and molecular modelling studies.

Guanylthiourea (GTU) derivatives were identified as possible anti-malarial agents, recently, using in vitro studies on Plasmodium falciparum. This article gives an account of the in vivo anti-malarial activity of GTU derivatives against experimental rodent malaria. A total of 20 synthesized GTU derivatives were evaluated for in vivo antimalarial activity, out of which six showed encouraging results; one compound appeared to have curative potential. Molecular docking and molecular dynamics analysis were carried out to understand the molecular level interactions.

Cross-Dehydrogenative Coupling of Heterocyclic Scaffolds with Unfunctionalized Aroyl Surrogates by Palladium(II) Catalyzed C(sp2)-H Aroylation through Organocatalytic Dioxygen Activation.

Cross-dehydrogenative coupling of biorelevant heterocyclic scaffolds with arylmethanes for aroylation during Pd(II)-catalyzed C(sp2)-H activation has been achieved through dioxygen activation by NHPI. Mass spectrometry and 1H NMR based kinetic isotope effect studies revealed C-H bond activation as the rate-determining step. Radical scavenging experiments indicated a radical pathway. The 1H NMR of an aliquot of reaction mixture and in situ trapping with 2-aminothiophenol revealed the formation of aldehyde during aerobic oxidation of the arylmethanes. The reaction has broad scope for different variations of the aroyl source and the directing group that includes benzothiazole, benzooxazole, pyridine, quinoxaline, pyrimidine, and azoarene. The benzylic methylene moiety was found to be the source of the aroyl carbon with the benzyl ether moiety being the most preferred followed by the carbonyl group of aryl aldehyde and the aryl methane. However, the ease of availability of aryl methanes makes them the most attractive as an aroyl source. A time dependent selective mono- and bis-aroylation can be achieved. The 1,3-diarylpyrimidines exhibited regioselective aroylation of the 2-phenyl moiety irrespective of the absence or presence of any substitutent (electron withdrawing or electron donating) in the 3-phenyl moiety. For unsymmetrical azoarenes, selective aroylation took place in the phenyl moiety bearing the substituent.

Molecular insight into atypical instability behavior of fixed-dose combination containing amlodipine besylate and losartan potassium.

Combination therapy with the use of fixed-dose combinations (FDCs) is evincing increasing interest of prescribers, manufacturers and even regulators, evidently due to the primary benefit of improved patient compliance. However, owing to potential of drug-drug interaction, FDCs require closer scrutiny with respect to their physical and chemical stability. Accordingly, the purpose of the present study was to explore stability behavior of a popular antihypertensive combination of amlodipine besylate (AML) and losartan potassium (LST). Physical mixtures of the two drugs and multiple marketed formulations were stored under accelerated conditions of temperature and humidity (40°C/75% RH) in a stability chamber and samples were withdrawn after 1 and 3 months. The physical changes were observed visibly, while chemical changes were monitored by HPLC employing a method that could separate the two drugs and all other components present. The combination revealed strong physical instability and also chemical degradation of AML in the presence of LST. Interestingly, three isomeric interaction products of AML were formed in the combination, which otherwise were reported in the literature to be generated on exposure of AML free base above its melting point. The same unusual products were even formed when multiple marketed FDCs were stored under accelerated conditions outside their storage packs. However, these were absent when AML alone was stored in the same studied conditions. Therefore, reasons for physical and chemical incompatibility and the mechanism of degradation of AML in the presence of LST were duly explored at the molecular level. The outcomes of the study are expected to help in development of stable FDCs of the two drugs.

Microwave Assisted Synthesis of Biorelevant Benzazoles.

The benzazole scaffolds are present in various therapeutic agents and have been recognized as the essential pharmacophore for diverse biological activities. These have generated interest and necessity to develop efficient synthetic methods of these privileged classes of compounds to generate new therapeutic leads for various diseases. The biological activities of the benzazoles and efforts towards their synthesis have been summarized in a few review articles. In view of these, the aim of this review is to provide an account of the developments that have taken place in the synthesis of biorelevant benzazoles under microwave irradiation as the application of microwave heating has long been recognized as a green chemistry tool for speedy generation of synthetic targets. Attention has been focused to those literature reports wherein the use of microwave irradiation is the key step in the formation of the heterocyclic ring system or in functionalization of the benzazole ring system to generate the essential pharmacophoric feature. The convenient and economic way to synthesize these privileged class of heterocycles through the use of microwave irradiation that would be beneficial for the drug discovery scientist to synthesize biologically active benzazoles and provide access to wide range of reactions for the synthesis of benzazoles constitute the theme of this review. Examples have been drawn wherein the use of microwave heating offers distinct advantage in terms of improved product yields and reduction of reaction time as compared to those observed for the synthesis under conventional heating.

Design, development of new synthetic methodology, and biological evaluation of substituted quinolines as new anti-tubercular leads.

Two series of quinoline-based compounds were designed, synthesised and evaluated for anti-tubercular activity against Mycobacterium tuberculosis H37Rv (ATCC 27294 strain). A new method for Friedländer quinoline synthesis has been developed in water under the catalytic influence of the Brønsted acid surfactant DBSA. Among the forty-two compounds tested for anti-TB activity, twenty-three compounds exhibited significant activity against the growth of M. tuberculosis (MIC 0.02-6.25µg/mL). In particular, the compounds 3b and 3c displayed excellent anti-TB activity with MIC values of 0.2 and 0.39µg/mL, respectively, and are more potent than the standard drugs E, Cfx and Z that are clinically used to treat TB. The cytotoxicity of the compounds with MIC ⩽6.25µg/mL was evaluated against Human Embryonic Kidney 293T cell lines and all of the active compounds were found to be nontoxic (<50% inhibition). The results suggest that the synthesised substituted quinolines are promising leads for development of new drug to treat TB.

Azine-Hydrazone Tautomerism of Guanylhydrazones: Evidence for the Preference Toward the Azine Tautomer.

Guanylhydrazones have been known for a long time and have wide applications in organic synthesis, medicinal chemistry, and material science; however, little attention has been paid toward their electronic and structural properties. Quantum chemical analysis on several therapeutically important guanylhydrazones indicated that all of them prefer the azine tautomeric state (by about 3-12 kcal/mol). A set of simple and conjugated azines were designed using quantum chemical methods, whose tautomeric preference toward the azine tautomer is in the range of 3-8 kcal/mol. Twenty new azines were synthesized and isolated in their neutral state. Variable temperature NMR study suggests existence of the azine tautomer even at higher temperatures with no traces of the hydrazone tautomer. The crystal structures of two representative compounds confirmed that the title compounds prefer to exist in their azine tautomeric form.