Hoda Y. Hassan

Synthesis of di- and tripeptide analogues containing α-ketoamide as a new core structure for inhibition of HIV-1 protease

Di- and tripeptide analogues containing alpha-ketoamide as a new core structure and incorporating allophenylnorstatine (Apns) as a transition state mimic, were designed and synthesized in the hope of obtaining a novel structural type of HIV-1 protease inhibitors. The immediate precursor, Apns-Thz-NHBu(t) was prepared by coupling of Boc-Apns with N-tert x butyl Thz-4-carboxamide hydrochloride. Removal of Boc group followed by coupling with the respective alpha-ketoacid residue (P2) gave the desired dipeptides (8-12) in almost quantitative yields. The alpha-keto tripeptides (18-21) were obtained by oxidation of the hydroxyl group of Apns (PI) in the appropriate tripeptide, iQOA-Val-Apns-(un)substituted Thz(Oxa)-NHBu(t) with DMSO/DCC. Preliminary evaluation of the activity of the synthesized derivatives was determined as percentage of enzyme inhibition at 5 microM and 50 nM levels of the di- and tripeptides respectively. The alpha-ketoamides displayed a significant enhanced potency relative to their parent isosteres as inhibitors of HIV-1 protease and are shown to be a promising new core structure for the development of enzyme inhibitors. A quantitative approach was attempted, using an LFE model, correlating the effect of structural modification and HIV-1 protease inhibition activity of the prepared dipeptides. The result indicates the contribution of the torsion angle by 84% to the activity of the inhibitors.

Fluorinated 1,2,4-Triazolo[1,5-a]pyrimidine-6-carboxylic Acid Derivatives as Antimycobacterial Agents

A series of fluorinated 1,2,4‐triazolo[1,5‐a]pyrimidine‐6‐carboxylic acid derivatives was designed and synthesized as fluoroquinolone analogues. The synthesized compounds were screened against Mycobacterium tuberculosis H37Rv strain at 6.25 μg/mL concentration. Compound 4, the 7‐oxo‐2‐(trifluoromethyl)‐4,7‐dihydro‐1,2,4‐triazolo[5,1‐a]pyrimidine‐6‐carboxylic acid was found to be a very potent inhibitor, being able to inhibit 92% growth of M. tuberculosis H37Rv at 6.25 μg/mL concentration. At the same time, it proofed to be nontoxic to mammalian cells (IC50 > 62.5 μg/mL in VERO cells).

Pharmacophoric model building for antitubercular activity of the individual Schiff bases of small combinatorial library

Synthesis and evaluation of anti-TB activity of individual compounds of Schiff bases combinatorial library were done against Mycobacterium tuberculosis H(37)Rv at a single concentration of 6.25mug/mL according to the protocol of TAACF. Compounds 2C and 3D produced 99% inhibitory activity on the investigated organism, while the other tested compounds showed lower activity ranging from 35 to 84%. It was found that there are no relation between the anti-TB activity of the tested compounds and their lipophilicity expressed by ClogP of these compounds. A 3D pharmacophoric model has been generated by Molecular Operating Environment (MOE) using a training set of 10 reported anti-TB compounds and testing the synthesized compounds (1A, 1B, 1D, 1E, 2C, 3A, 3C, 3D, 3E and 4A-4E). The generated pharmacophoric features include, F1: hydrogen bond donors (Don), F2: aromatic rings (Aro), F3: hydrogen bond acceptors (Acc)/metal ligator (ML), F4: Aro/hydrophobic (Hyd). In all hit set, it was found that the amidic nitrogen CONH-NC fitted the region of the Don, F1, while the amidic carbonyl group fitted the region of the Acc/ML, F3. The distances bridging F1 to F2, F3 and F4 were essential for anti-TB activity in the developed pharmacophore model, as it was confirmed from model validation procedure.

Spectrophotometric determination of some dibenzazepines

Abstract Simple and sensitive method is proposed for determination of four di-benzazepine derivatives. The method is based on the oxidation of dibenzazepines by potassium dichromate in acid medium. The reaction was followed spectrophoto-metrically by measuring the rate of change in absorbance of the coloured products at 670 nm. Linear calibration graphs from 5-50 μg/ml of the final solutions are obtained for all the studied drugs. The method has been successfully applied to the determination of dibenzazepines in some commercial and laboratory prepared tablets. The results were compared statistically with those obtained by official procedures.

Spectrophotometric determination of some dibenzazepine drugs by electrophilic coupling

Two sensitive spectrophotometric methods for the determination of imipramine hydrochloride, clomipramine hydrochloride, desipramine hydrochloride, and trimipramine maleate in bulk and in dosage forms are described. The first method is based on the interaction of diazotized p-nitroaniline (DPNA) with the dibenzazepine drug in 5M hydrochloric acid. The second is based on the oxidative coupling of the dibenzazepine drug with 3-methylbenzothiazolin-2-one hydrazone (MBTH) in the presence of ammonium iron(III) sulphate in 0.1M hydrochloric acid. The resulting chromophores are measured at 575 nm (for the DPNA method) or at 620-630 nm (for the MBTH method), and are stable for at least 24 hr. The commonly encountered excipients and additives do not interfere with the determinations. Results from the analysis of pure drugs, commercial tablets and laboratory-prepared tablets by these methods agree well with those of official methods.

Spectrophotometric determination of some dibenzazepines with picryl chloride

A simple and sensitive spectrophotometric method has been developed for the determination of some dibenzazepines, based on reaction with picryl chloride in chloroform medium and measurement at 395 nm. Beers law is obeyed in concentration ranges 0.1-1.0 microg/ml for imipramine hydrochloride, trimipramine maleate and opipramol dihydrochloride, 0.16-1.6 microg/ml for desipramine hydrochloride and 0.4-2.4 microg/ml for clomipramine hydrochloride. The method was applied successfully to the determination of dibenzazepines in tablets and the results were comparable to those obtained by official procedures.

Utility of Certain π-Acceptors for the Spectrophotometric Determination of Isoniazid

Abstract The interaction of isoniazid with three selected π-acceptors in an aqueous-acetonitrile solution of pH 9.0–9.5 was found to give intensely coloured products. A spectrophotometric method based on this reaction is described for quantitation of isoniazid. The determination of products was carried out at 445 nm for chloranil, 450 nm for bromanil and around 750 nm for 7,7,8,8-tetracyanoquinodimethane. The effect of several variables on the colour development was studied. The molecular ratios of the reactants have been established. The proposed methods have been applied successfully for analysis of isoniazid in pure samples and in a number of its pharmaceutical preparations with good accuracy and precision. Results were compared to those obtained by the official methods.

Use of 7,7,8,8-tetracyanoquinodimethane for spectrophotometric determination of certain local anaesthetics and procainamide hydrochloride

A simple and rapid spectrophotometric procedure has been developed for the determination of four local anaesthetics containing a free primary amine moiety and of procainamide hydrochloride as the drug substances and in dosage forms. The method is based on the reaction of the drug with 7,7,8,8-tetracyanoquinodimethane in alkaline solution to produce yellow products. The chromogen was measured at 473 nm. The effects of several variables on colour development were established. Jobs plots of absorbance versus molar ratio of drug to reagent indicated a 1:1 ratio for all the drugs studied. Results of the analysis of drug substances and their dosage forms by the proposed method are in good agreement with those obtained by the USP XX method.

Synthesis, antimicrobial activity and molecular modeling study of 3-(5-amino-(2H)-1,2,4-triazol-3-yl]-naphthyridinones as potential DNA-gyrase inhibitors

Four series of triazolylnaphthyridinone derivatives were synthesized as structural surrogates of nalidixic acid. The targeted derivatives involve: 3-(5-acylamino-2H-1,2,4-triazol-3-yl)-naphtyridin-4-ones 6(a-e); 3-(5-benzylidineamino-2H-1,2,4-triazol-3-yl)-naphthyridin-4-ones 8(a-g) and their 6-bromonaphthyridin-4-one analogs 7(a-e); 9(a-g). The synthesized compounds were evaluated In vitro for their antimicrobial activity against selected resistant strains of G+ve, G-ve, and Mycobacterium phlei. The results revealed remarkable selectivity, of the tested compounds, against Bacillus subtilis and Aggregatibacter actinomycetemcomitans, which are resistant to nalidixic acid. The growth inhibition zones were ranging from 20 to 40 mm at 10 mg/ml and the respective MIC-values ∼3.68-6.3 µM. The results illustrate that the 6-bromo derivatives 7(a-e) and 9(a-g) were more potent than the non-brominated counterparts 6(a-e) and 8(a-e) respectively. Inhibition of E. coli DNA-gyrase supercoiling activity is also evaluated. The 5-(4-methoxybanzamido)-triazolyl-6-bromonaphthyridinone (7e) exhibits IC50 = 1.94 μg/ml, which is comparable to that of nalidixic acid (IC50: 1.74 μg/ml). In addition, the most prominent IC50-values are displayed by: (7a;IC50: 2.77 μg/ml); (8g; IC50: 3.78 μg/ml); and (9d;IC50: 3.21 μg/ml). Molecular docking to the active site of DNA-gyrase cleavage complex of Acinetobacter baumannii (PDB code: 2xkk) co-crystallized with moxifloxacin revealed similar binding modes in addition to new interactions. Assessment of drug-likeness characteristics illustrate that the synthesized compounds showed agreement to Lipinskis and Vepers parameters. The study could offer an exceptional framework that may lead to the discovery of new potent antimicrobial agents.