Mahamadhanif S. Shaikh

Design and synthesis of novel carbazolo–thiazoles as potential anti-mycobacterial agents using a molecular hybridization approach

Various substituted carbazolo–thiazoles (compounds 6a–6o) were synthesized in good yields using a molecular hybridization approach. The synthesized compounds were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain at the National Institute of Allergy and Infectious Diseases (Bethesda, MD, USA). Among the tested series, compound 6c (minimum inhibitory concentration 21 μM) showed the most promising anti-mycobacterial activity. Brief structure–activity relationship studies showed that the electron-donating groups (OCH3 and OH), particularly on the phenyl ring of the thiazole motif, had a positive correlation with the anti-mycobacterial activity. In addition, they displayed low cytotoxicity against a mammalian Vero cell line using the MTT assay, thereby having a high therapeutic index. This study shows the importance of molecular hybridization and the scope for the development of carbazole–thiazole compounds as potential anti-mycobacterial agents.

Synthesis of novel 4-nitropyrrole-based semicarbazide and thiosemicarbazide hybrids with antimicrobial and anti-tubercular activity.

We report the synthesis and screening of forty novel 4-nitropyrrole-semicarbazide conjugates inspired from the reported bio-potential of bromopyrrole alkaloids and semicarbazide derivatives for antimicrobial activity. Herein, hybrids 5k-5o, 5r, 5s and 5t displayed four-fold increased activity (MIC=0.39 μg/mL) against Escherichia coli compared to standard ciprofloxacin. Eight hybrids, 5k-5o and 5r-5t displayed equal antibacterial activity (MIC=1.56 μg/mL) against Klebsiella pneumonia compared to standard ciprofloxacin. Hybrid, 5k-5o (MIC=0.195 μg/mL) displayed highly potent antibacterial activity against MSSA as compared to standard ciprofloxacin. Eight-fold superior activity was observed for four hybrids 5k-5m and 5o (MIC=0.39 μg/mL) against MRSA. Further, nine hybrids displayed four-fold superior antifungal activity (MIC=0.78 μg/mL) compared to standard Amphotericin B. Encouraging MICs of these hybrids recognize them as promising leads for development of potential antimicrobial drugs.

A Recent Perspective on Discovery and Development of Diverse Therapeutic Agents Inspired from Isatin Alkaloids

Isatin as an alkaloidal framework have consistently attracted attention of medicinal chemist towards development of wide range of novel therapeutic agents. This review report has discussed significant isatin lead molecules and their derivatives which have shown promising biological potential in recent times. The substituted isatins showing a potent pharmacological activities such as antimicrobial, antitubercular, anticancer, antioxidant, anti-histaminic, anti-HIV, antiviral, anti-inflammatory, anti-Parkinsons and antidiabetic have been described in this review. The mechanism of action leading to therapeutic activity of the respective isatin derivation has also been recorded. This review reveals that the systematic and rational modifications on isatin motif exhibited significant bio-activities which can be exploited for the development of potent novel therapeutic agents in the future studies. Hence the quest to investigate more structural alterations on isatin scaffold should be continued.

Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents

Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = <0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.

Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents.

A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1,3,4-oxadiazol-2(3H)-thione (4a-k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)-thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a-k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4thh, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand-protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC50 values.

An appraisal on recent medicinal perspective of curcumin degradant: Dehydrozingerone (DZG).

Natural products serve as a key source for the design, discovery and development of potentially novel drug like candidates for life threatening diseases. Curcumin is one such medicinally important molecule reported for an array of biological activities. However, it has major drawbacks of very poor bioavailability and solubility. Alternatively, structural analogs and degradants of curcumin have been investigated, which have emerged as promising scaffolds with diverse biological activities. Dehydrozingerone (DZG) also known as feruloylmethane, is one such recognized degradant which is a half structural analog of curcumin. It exists as a natural phenolic compound obtained from rhizomes of Zingiber officinale, which has attracted much attention of medicinal chemists. DZG is known to have a broad range of biological activities like antioxidant, anticancer, anti-inflammatory, anti-depressant, anti-malarial, antifungal, anti-platelet and many others. DZG has also been studied in resolving issues pertaining to curcumin since it shares many structural similarities with curcumin. Considering this, in the present review we have put forward an effort to revise and systematically discuss the research involving DZG with its biological diversity. From literature, it is quite clear that DZG and its structural analogs have exhibited significant potential in facilitating design and development of novel medicinally active lead compounds with improved metabolic and pharmacokinetic profiles.

Design, synthesis and QSAR studies of 2-amino benzo[d]thiazolyl substituted pyrazol-5-ones: novel class of promising antibacterial agents

Novel analogs of 3-(4-substituted benzylideneamino)-N-(6-substituted-1,3-benzo[d]thiazol-2-yl)-4,5-dihydro-5-oxo-pyrazole-1-carboxamide (5a–s) were designed and synthesized by reacting 3-amino-N-(6-substituted-1,3-benzo[d]thiazol-2-yl)-4,5-dihydro-5-oxo-pyrazole-1-carboxamide (4a–d) with p-substituted benzaldehydes. The Infrared Spectroscopy, 1H-Nuclear Magnetic Resonance, 13C-Nuclear Magnetic Resonance, and High Resolution Mass Spectra spectral data confirmed the structures of all the novel synthesized compounds. Among the series tested, two compounds 5k and 5o displayed promising antibacterial activity especially against Staphylococcus aureus (MIC = 3.14 and 1.57 µg/mL) and Bacillus subtilis (MIC = 3.12 and 1.84 µg/mL) respectively. Further, these title compounds were also assessed for their cytotoxic activity (IC50) against mammalian Vero cell line using 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl-tetrazolium bromide assay, indicating that the compounds exhibit antibacterial activity at non-cytotoxic concentrations. Field based three-dimensional quantitative structure–activity relationships were also discussed based on the antimicrobial screening data.Graphical AbstractSynthesis, spectral studies, antibacterial evaluation and QSAR studies of nineteen novel Schiff bases of pyrazol-5-one derivatives derived from 2-aminobenzothiazole nucleus are described.

Discovery of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as potent and orally efficacious microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors: Part-1

This letter describes the synthesis and biological evaluation of furan and dihydrofuran-fused tricyclic benzo[d]imidazole derivatives as novel mPGES-1 inhibitors, capable of inhibiting an increased PGE2 production in the disease state. Structure-activity optimization afforded many potent mPGES-1 inhibitors having <50 nM potencies in the A549 cellular assay and adequate metabolic stability in liver microsomes. Lead compounds 8l and 8m demonstrated reasonable in vitro pharmacology and pharmacokinetic properties over other compounds. In particular, 8m revealed satisfactory oral pharmacokinetics and bioavailability in multiple species like rat, guinea pig, dog and cynomolgus monkey. In addition, the representative compound 8m showed in vivo efficacy by inhibiting LPS-induced thermal hyperalgesia with an ED50 of 14.3 mg/kg in guinea pig.

Tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives as microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors: SAR and in vivo efficacy in hyperalgesia pain model

A series of substituted tricyclic 4,4-dimethyl-3,4-dihydrochromeno[3,4-d]imidazole derivatives have been synthesized and their mPGES-1 biological activity has been disclosed in detail. Structure-activity relationship (SAR) optimization provided inhibitors with excellent mPGES-1 potency and low to moderate PGE2 release A549 cell potency. Among the mPGES-1 inhibitors studied, 7, 9 and 11l provided excellent selectivity over COX-2 (>200-fold) and >70-fold selectivity for COX-1 except 11l, which exhibited dual mPGES-1/COX-1 activity. Furthermore, the above tested mPGES-1 inhibitors demonstrated good metabolic stability in liver microsomes, high plasma protein binding (PPB) and no significant inhibition observed in clinically relevant CYP isoforms. Besides, selected mPGES-1 tool compounds 9 and 11l provided good in vivo pharmacokinetic profile and oral bioavailability (%F=33 and 85). Additionally, the representative mPGES-1 tool compounds 9 and 11l revealed moderate in vivo efficacy in the LPS-induced thermal hyperalgesia guinea pig pain model.

Novel synthetic organic compounds inspired from antifeedant marine alkaloids as potent bacterial biofilm inhibitors.

In this paper, we have reported seventeen novel synthetic organic compounds derived from marine bromopyrrole alkaloids, exhibiting potential inhibition of biofilm produced by Gram-positive bacteria. Compound 5f with minimumbiofilm inhibitory concentration(MBIC) of 0.39, 0.78 and 3.125 μg/mL against MSSA, MRSA and SE respectively, emerged as promising anti-biofilm lead compounds. In addition, compounds 5b, 5c, 5d, 5e, 5f, 5h, 5i and 5j revealed equal potency as that of the standard drug Vancomycin (MBIC = 3.125 μg/mL) against Streptococcus epidermidis. Notably, most of the synthesized compounds displayed better potency than Vancomycin indicating their potential as inhibitors of bacterial biofilm. The cell viability assay for the most active hybrid confirms its anti-virulence properties which need to be further researched.