Nadia M. Mahfouz

Design, synthesis and antiinflammatory activity of some 1,3,4-oxadiazole derivatives

A series of substituted 1,3,4-oxadiazole derivatives 19-34 were synthesized as antiinflammatory agents. The target compounds were obtained by cyclodesulfurization of the corresponding thiosemicarbazides 3-18 using either dicyclohexylcarbodiimide DCC, or I(2)/NaOH. Intermediates 3-18 are readily accessible through conversion of the carboxylic acids 1a-d to the respective hydrazides 2a-d followed by treatment with appropriate isothiocyanate derivatives. The structures of the synthesized compounds were confirmed by elemental as well as spectroscopic analyses. The antiinflammatory activity was investigated by determination of the inhibitory effects of the oxadiazole derivatives 19-34 on histamine-induced edema in rat abdomen. Compounds 19a, 21a, 23b, 28c and 32d proved to be more potent antiinflammatory agents at 200 mg/kg po than ibuprofen, the standard reference drug. Other compounds such as 20a, 25b, 27c, 29c, and 33d showed significant antiinflammatory activity but less than ibuprofen at the same dose level. The low toxicity of the most potent compounds was reflected by their higher LD(50) value, ranging from ~1000 to 1500 mg/kg, as well as the lower ulcerogenic liability at 200 mg/kg po. Furthermore, some of the newly synthesized derivatives were better analgesics than the reference drug as observed from the percentage writhing inhibition in the p-benzoquinone (PBQ)-induced writhing test in mice.

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.

Cyclic amide derivatives as potential prodrugs II: N-hydroxymethylsuccinimide- / isatin esters of some NSAIDs as prodrugs with an improved therapeutic index.

Ester prodrugs of aspirin 1a, ibuprofen 1b, naproxen 1c and indomethacin 1d were synthesized using N-Hydroxymethylsuccinimide (HMSI) 3 and N-hydroxymethylisatin (HMIS) 4 as promoieties to reduce their gastrointestinal toxicity and improve bioavailability. Additionally, the kinetics of hydrolysis of the synthesized prodrugs 5a-d and 6a-d were studied at 37 degrees C in non-enzymatic simulated gastric fluid (SGF; hydrochloric acid buffer pH = 1.2); 0.02 M phosphate buffer (pH = 7.4); 80% human plasma and 10% rat liver homogenate. The results indicate higher chemical stability of the ester prodrugs in non-enzymatic SGF (t(1/2) congruent with 6.5-18.6 h) and rapid conversion to the parent drugs in 80% human plasma (t(1/2) congruent with 11.4-235 min) as well as in 10% rat liver homogenates (t(1/2) congruent with 12.0-90.0 min). As a general pattern, the HMSI esters 5a-d revealed higher chemical stability than the corresponding HMIS analogues 6a-d. The pH-rate profile of 5c and 6a indicated maximum stability of the former at pH = 1.2-8.0 and of the latter at pH = 1.2-4.0. The distribution coefficient (D(7.4)) values of the prodrugs 5a-d, 6a-d and the parent drugs 1a-d in an n-octanol/phosphate buffer (pH = 7.4) system indicated enhanced lipophilic properties of the prodrugs. Furthermore, the HMIS ester prodrugs 6a-d are more lipophilic than the corresponding HMSI derivatives 5a-d. In vivo ulcerogenicity studies using scanning electron microscopy on stomach specimens of rats treated with an oral dose for 4 d revealed that the synthesized ester prodrugs are significantly less irritating to gastric mucosa than the parent drugs. These results suggested HMSI and/or HMIS esters possess good potential as prodrugs with an improved therapeutic index for oral delivery of NSAIDs.

Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility

A series of amino acid esters (3a‐e) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N‐diethylglycinate hydrochloride (3a) and 4‐ethylpiperazinoacetate (3e) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4‐phenylpiperazinoacetate derivative (3f), which was 6.5‐times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80% human plasma at 37°C. In all cases the hydrolysis followed pseudo‐first‐order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half‐life, t12, 4–16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutes to metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t12 values were approximately 2.5 and 8.5 h, respectively. A comparative pH‐rate profile study of N,N‐diethylglycinate hydrochloride (3a) and 4‐ethylpiperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2–10 was investigated. The results indicated that 3a showed marked stability at pH 2–6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in‐vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug‐treated animals (10‐ and 2.5‐fold) as compared with the parent drug‐treated group. In conclusion, the designed amino acid esters 3a and 3c‐e might be considered as good candidates for water‐soluble prodrug forms of metronidazole.

Synthesis and Three-dimensional Qualitative Structure Selectivity Relationship of 3,5-Disubstituted-2,4-Thiazolidinedione Derivatives As COX2 Inhibitors

In our effort for synthesis of selective COX2 inhibitors, certain new 2,4-thiazolidinedione derivatives were synthesized. It necessitates preparation of potassium salt of 2,4-thiazolidinedione 2, which condensed with intermediate 4a. The resulting 3-[2-(4-methylphenyl)-2-oxo-1-phenylethyl]-2,4-thiazolidinedione 8 was condensed with appropriate aldehyde to afford compounds 10a, 10i-l, 10o and 10p. Compounds (9a-l, 10a-n, 10p, 11 and 12) were obtained through the preparation of 5-arylmethylidene-2,4-thiazolidinediones 6a-p and reaction of its potassium salt 7a-p with compounds 4a, 4b, and 5. Some compounds displayed significant analgesic activity as compared to reference standards. The anti-inflammatory activity of the synthesized compounds revealed that intermediate 8 and compounds 9c, 10c and 10d showed good results. Compound 10c produced no significant mucosal injury. HipHop methodology of Catalyst program was used to build up hypothetical model of selective COX2 inhibitors followed by fitting the synthesized compounds to this model. Compounds 10c and 10d were suspected to be promising selective COX2 inhibitors. Also, compounds (6c, 8, 9a,c,d,k, 10a,c,d,k, 11 and 12) were docked into COX1 and COX2 X-ray structures, using DOCK6 program. Docking results suggested that several of these derivatives are active COX inhibitors with a significant preference for COX2.

Quantitative structure–activity relationship (QSAR) studies on a series of 1,3,4-thiadiazole-2-thione derivatives as tumor-associated carbonic anhydrase IX inhibitors

A linear quantitative structure–activity relationship (QSAR) study that encodes various aspects of physicochemical, topological and electronic descriptors has been developed for a series of 1,3,4-thiadiazole-2-thione derivatives (1a-r and 2a-c). The carbonic anhydrase IX inhibitory activity of the candidates under study (1a-r and 2a-c) were correlated to the selected parameters using stepwise linear regression analyses to achieve the best QSAR model. Promising results were obtained with the employed tetra-parametric model indicating that the information approach used in the present investigation is quite useful for modeling carbonic anhydrase IX inhibitors.